Substituted aminoalcohols useful in treatment of Alzheimer&#39;s disease

ABSTRACT

The invention provides compounds of formula (I): useful in treating Alzheimer&#39;s disease and other similar diseases. These compounds include inhibitors of the beta-secretase enzyme that are useful in the treatment of Alzheimer&#39;s disease and other diseases characterized by deposition of A beta peptide in a mammal. The compounds of the invention are useful in pharmaceutical compositions and methods of treatment to reduce A beta peptide formation

This application claim priority to U.S. Provisional Application Ser. No.60/297,420 filed Jun. 11, 2001

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention is relates to substituted aminoalcohols and to suchcompounds that are useful in treatment of Alzheimer's disease andsimilar diseases, more specifically it relates to such compounds thatinhibit β-secretase, an enzyme that cleaves amyloid precursor protein toproduce Aβ peptide, a major component of the amyloid plaques found inthe brains of Alzheimer's sufferers.

2. Description of the Related Art

Alzheimer's disease (AD) is a progressive degenerative disease of thebrain primarily associated with aging. Clinical presentation of AD ischaracterized by loss of memory, cognition, reasoning, judgement, andorientation. As the disease progresses, motor, sensory, and linguisticabilities are also affected until there is global impairment of multiplecognitive functions. These cognitive losses occur gradually, buttypically lead to severe impairment and eventual death in the range offour to twelve years.

Alzheimer's disease is characterized by two major pathologicobservations in the brain: neurofibrillary tangles and beta amyloid (orneuritic) plaques, comprised predominantly of an aggregate of a peptidefragment know as A beta. Individuals with AD exhibit characteristicbeta-amyloid deposits in the brain (beta amyloid plaques) and incerebral blood vessels (beta amyloid angiopathy) as well asneurofibrillary tangles. Neurofibrillary tangles occur not only inAlzheimer's disease but also in other dementia-inducing disorders. Onautopsy, large numbers of these lesions are generally found in areas ofthe human brain important for memory and cognition.

Smaller numbers of these lesions in a more restricted anatomicaldistribution are found in the brains of most aged humans who do not haveclinical AD. Amyloidogenic plaques and vascular amyloid angiopathy alsocharacterize the brains of individuals with Trisomy 21 (Down'sSyndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of theDutch-Type (HCHVA-D), and other neurogenerative disorders. Beta-amyloidis a defining feature of AD, now believed to be a causative precursor orfactor in the development of disease. Deposition of A beta in areas ofthe brain responsible for cognitive activities is a major factor in thedevelopment of AD. Beta-amyloid plaques are predominantly composed ofamyloid beta peptide (A beta, also sometimes designated betaA4). A betapeptide is derived by proteolysis of the amyloid precursor protein (APP)and is comprised of 39-42 amino acids. Several proteases calledsecretases are involved in the processing of APP.

Cleavage of APP at the N-terminus of the A beta peptide bybeta-secretase and at the C-terminus by one or more gamma-secretasesconstitutes the beta-amyloidogenic pathway, i.e. the pathway by which Abeta is formed. Cleavage of APP by alpha-secretase produces alpha-sAPP,a secreted form of APP that does not result in beta-amyloid plaqueformation. This alternate pathway precludes the formation of A betapeptide. A description of the proteolytic processing fragments of APP isfound, for example, in U.S. Pat. Nos. 5,441,870; 5,721,130; and5,942,400.

An aspartyl protease has been identified as the enzyme responsible forprocessing of APP at the beta-secretase cleavage site. Thebeta-secretase enzyme has been disclosed using varied nomenclature,including BACE, Asp, am Mamepsin. See, for example, Sindla et.al., 1999,Nature 402:537-554 (p501) and published PCT application WO00/17369.

Several lines of evidence indicate that progressive cerebral depositionof beta-amyloid peptide (A beta) plays a seminal role in thepathogenesis of AD and can precede cognitive symptoms by years ordecades. See, for example, Selkoe, 1991, Neuron 6:487. Release of A betafrom neuronal cells grown in culture and the presence of A beta incerebrospinal fluid (CSF) of both normal individuals and AD patients hasbeen demonstrated. See, for example, Seubert et al., 1992, Nature359:325-327.

It has been proposed that A beta peptide accumulates as a result of APPprocessing by beta-secretase, thus inhibition of this enzyme's activityis desirable for the treatement of AD. In vivo processing of APP at thebeta-secretase cleavage site is thought to be a rate-limiting step in Abeta production, and is thus a therapeutic target for the treatment ofAD. See for example, Sabbagh, M., et al., 1997, Alz. Dis. Rev. 3, 1-19.

BACE1 knockout mice fail to produce A beta, and present a normalphenotype. When crossed with transgenic mice that overexpress APP, theprogeny show reduced amounts of A beta in brain extracts as comparedwith control animals (Luo et.al., 2001 Nature Neuroscience 4:231-232).This evidence further supports the proposal that inhibition ofbeta-secretase activity and reduction of A beta in the brain provides atherapeutic method for the treatment of AD and other beta amyloiddisorders.

Published PCT application WO00/47618 entitled “Beta-Secretase EnzymeCompositions and Methods” identifies the beta-secretase enzyme andmethods of its use. This publication also discloses oligopeptideinhibitors that bind the enzyme's active site and are useful in affinitycolumn purification of the enzyme. In addition, WO00/77030 disclosestetrapeptide inhibitors of beta-secretase activity that are based on astatine molecule

Various pharmaceutical agents have been proposed for the treatment ofAlzheimer's disease but without any real success. U.S. Pat. No.5,175,281 discloses 21-aminosteroids as being useful for treatingAlzheimer's disease. U.S. Pat. No. 5,502,187 discloses bicyclicheterocyclic amines as being useful for treating Alzheimer's disease.

The hydroxyethylamine “nucleus” or isostere, of which the compounds ofthe invention is a truncated analog, has been used with success in thearea of HIV protease inhibition. Many of these hydroxyethylaminecompounds are known as well as how to make them. See for example, J. Am.Chem. Soc., 93,288-291 (1993), Tetrahedron Letters, 28(45) 5569-5572(1987), J. Med. Chem., 38(4), 581-584 (1994), Tetrahedron Letters,38(4), 619-620 (1997). European Patents, numbers 702 004, 678 503, 678514, 678 503 and 716077 by Maibaum, et al. are directed to similarisosteric strategies directed at renin inhibition. See also, U.S. Pat.Nos. 5,606,078 and 5,559,111, both to Goschke, et. al.; U.S. Pat. No.5,719,141, to Rasetti, et. al.; and U.S. Pat. No. 5,641,778, to Maibaum,et. al.

At present there are no effective treatments for halting, preventing, orreversing the progression of Alzheimer's disease. Therefore, there is anurgent need for pharmaceutical agents capable of slowing the progressionof Alzheimer's disease and/or preventing it in the first place.

Compounds that are effective inhibitors of beta-secretase, that inhibitbeta-secretase-mediated cleavage of APP, that are effective inhibitorsof A beta production, and/or are effective to reduce amyloid betadeposits or plaques, are needed for the treatment and prevention ofdisease characterized by amyloid beta deposits or plaques, such as AD.

SUMMARY OF THE INVENTION

In a broad aspect, the invention provides substituted aminoalcohols offormula (I):

or pharmaceutically acceptable salts or esters thereof,

-   wherein B is H, C₁-C₁₀ straight or branched chain alkyl;-   wherein R₂₀ is H or C₁₋₆ alkyl or alkenyl-   wherein n is 0 or 1;-   wherein R₁ is:    -   (I) C₁-C₆ alkyl, optionally substituted with one, two or three        substituents selected from the group consisting of C₁-C₃ alkyl,        C₁-C₇ alkyl (optionally substituted with C₁-C₃ alkyl and C₁-C₃        alkoxy), —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆        alkyl, —OC═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as        defined above,    -   (II) —CH₂—S(O)₀₋₂—(C₁-C₆ alkyl),    -   (III) —CH₂—CH₂—S(O)₀₋₂—(C₁-C₆ alkyl),    -   (IV) C₂-C₆ alkenyl with one or two double bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl,    -   (V) C₂-C₆ alkynyl with one or two triple bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl,    -   (VI) —(CH₂)_(n1)—(R_(1-aryl)) where n₁ is zero or one and where        R_(1-aryl) is phenyl, 1-naphthyl, 2-naphthyl and indanyl,        indenyl, dihydronaphthalyl, tetralinyl optionally substituted        with one, two, three or four of the following substituents on        the aryl ring:        -   (A) C₁-C₆ alkyl optionally substituted with one, two or            three substituents selected from the group consisting of            C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b)            where R_(1-a) and R_(1-b) are as defined above, —C≡N, —CF₃,            C₁-C₃ alkoxy,        -   (B) C₂-C₆ alkenyl with one or two double bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁-C₆ alkyl,        -   (C) C₂-C₆ alkynyl with one or two triple bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁-C₆ alkyl,        -   (D) —F, Cl, —Br and —I,        -   (F) —C₁-C₆ alkoxy optionally substituted with one, two or            three —F,        -   (G) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as            defined below,        -   (H) —OH,        -   (I) —C≡N,        -   (J) C₃-C₇ cycloalkyl, optionally substituted with one, two            or three substituents selected from the group consisting of            —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,            —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆            alkyl,        -   (K) —CO—(C₁-C₄ alkyl),        -   (L) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above,        -   (M) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above, or        -   (N) —SO₂—(C₁-C₄ alkyl),    -   (VII) —(CH₂)_(n1)—(R_(1-heteroaryl)) where n₁ is as defined        above and where R_(1-heteroaryl) is selected from the group        consisting of:        -   (A) pyridinyl,        -   (B) pyrimidinyl,        -   (C) quinolinyl,        -   (F) benzothienyl,        -   (G) indolyl,        -   (H) indolinyl,        -   (I) pryidazinyl,        -   (J) pyrazinyl,        -   (K) isoindolyl,        -   (L) isoquinolyl,        -   (M) quinazolinyl,        -   (N) quinoxalinyl,        -   (O) phthalazinyl,        -   (P) imidazolyl,        -   (Q) isoxazolyl,        -   (R) pyrazolyl,        -   (S) oxazolyl,        -   (T) thiazolyl,        -   (U) indolizinyl,        -   (V) indazolyl,        -   (W) benzothiazolyl,        -   (X) benzimidazolyl,        -   (Y) benzofuranyl,        -   (Z) furanyl,        -   (AA) thienyl,        -   (BB) pyrrolyl,        -   (CC) oxadiazolyl,        -   (DD) thiadiazolyl,        -   (EE) triazolyl,        -   (FF) tetrazolyl,        -   (II) oxazolopyridinyl,        -   (JJ) imidazopyridinyl,        -   (KK) isothiazolyl,        -   (LL) naphthyridinyl,        -   (MM) cinnolinyl,        -   (NN) carbazolyl,        -   (OO) beta-carbolinyl,        -   (PP) isochromanyl,        -   (QQ) chromanyl,        -   (SS) tetrahydroisoquinolinyl,        -   (TT) isoindolinyl,        -   (UU) isobenzotetrahydrofuranyl,        -   (VV) isobenzotetrahydrothienyl,        -   (WW) isobenzothienyl,        -   (XX) benzoxazolyl,        -   (YY) pyridopyridinyl,        -   (ZZ) benzotetrahydrofuranyl,        -   (AAA) benzotetrahydrothienyl,        -   (BBB) purinyl,        -   (CCC) benzodioxolyl,        -   (DDD) triazinyl,        -   (EEE) phenoxazinyl,        -   (FFF) phenothiazinyl,        -   (GGG) pteridinyl,        -   (HHH) benzothiazolyl,        -   (III) imidazopyridinyl,        -   (JJJ) imidazothiazolyl,        -   (KKK) dihydrobenzisoxazinyl,        -   (LLL) benzisoxazinyl,        -   (MMM) benzoxazinyl,        -   (NNN) dihydrobenzisothiazinyl,        -   (OOO)benzopyranyl,        -   (PPP) benzothiopyranyl,        -   (QQQ) coumarinyl,        -   (RRR) isocoumarinyl,        -   (SSS) chromonyl,        -   (TTT) chromanonyl, and        -   (UUU) pyridinyl-N-oxide,        -    where the R_(1-heteroaryl) group is bonded to —(CH₂)_(n1)—            by any ring atom of the parent R_(N-heteroaryl) group            substituted by hydrogen such that the new bond to the            R_(1-heteroaryl) group replaces the hydrogen atom and its            bond, where heteroaryl is optionally substituted with one,            two, three or four of:        -   (1) C₁-C₆ alkyl optionally substituted with one, two or            three substituents selected from the group consisting of            C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b)            where R_(1-a) and R_(1-b) are as defined above, —C≡N, —CF₃,            C₁-C₃ alkoxy,        -   (2) C₂-C₆ alkenyl with one or two double bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁-C₆ alkyl,        -   (3) C₂-C₆ alkynyl with one or two triple bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁-C₆ alkyl,        -   (4) —F, Cl, —Br and —I,        -   (6) —C₁-C₆ alkoxy optionally substituted with one, two, or            three —F,        -   (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as            defined below,        -   (8) —OH,        -   (9) —C≡N,        -   (10) C₃-C₇ cycloalkyl, optionally substituted with one, two            or three substituents selected from the group consisting of            —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,            —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆            alkyl,        -   (11) —CO—(C₁-C₄ alkyl),        -   (12) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above,        -   (13) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above, or        -   (14) —SO₂—(C₁-C₄ alkyl), with the proviso that when n, is            zero R_(1-heteroaryl) is not bonded to the carbon chain by            nitrogen,    -   (VIII) —(CH₂)_(n1)—(R_(1-heterocycle)) where n₁ is as defined        above and R_(1-heterocycle) is selected from the group        consisting of:        -   (A) morpholinyl,        -   (B) thiomorpholinyl,        -   (C) thiomorpholinyl S-oxide,        -   (D) thiomorpholinyl S,S-dioxide,        -   (E) piperazinyl,        -   (F) homopiperazinyl,        -   (G) pyrrolidinyl,        -   (H) pyrrolinyl,        -   (I) tetrahydropyranyl,        -   (J) piperidinyl,        -   (K) tetrahydrofuranyl,        -   (L) tetrahydrothienyl,        -   (M) homopiperidinyl,        -   (N) homomorpholinyl,        -   (O) homothiomorpholinyl,        -   (P) homomorpholinyl S-oxide,        -   (Q) homothiomorpholinyl S,S-dioxide, and        -   (R) oxazolidinonyl,        -    where the R_(1-heterocycle) group is bonded by any atom of            the parent R_(1-heterocycle) group substituted by hydrogen            such that the new bond to the R_(1-heterocycle) group            replaces the hydrogen atom and its bond, where heterocycle            is optionally substituted with one, two, three or four of:            -   (1) C₁-C₆ alkyl optionally substituted with one, two or                three substituents selected from the group consisting of                C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,                —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as                defined above, —C≡N, —CF₃, C₁-C₃ alkoxy,            -   (2) C₂-C₆ alkenyl with one or two double bonds,                optionally substituted with one, two or three                substituents selected from the group consisting of —F,                —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,                —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or                C₁-C₆ alkyl,            -   (3) C₂-C₆ alkynyl with one or two triple bonds,                optionally substituted with one, two or three                substituents selected from the group consisting of —F,                —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,                —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or                C₁-C₆ alkyl,            -   (4) —F, Cl, —Br and —I,            -   (5) C₁-C₆ alkoxy,            -   (6) —C₁-C₆ alkoxy optionally substituted with one, two,                or three —F,            -   (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as                defined below,            -   (8) —OH,            -   (9) —C≡N,            -   (10) C₃-C₇ cycloalkyl, optionally substituted with one,                two or three substituents selected from the group                consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃                alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are                —H or C₁-C₆ alkyl,            -   (11) —CO—(C₁-C₄ alkyl),            -   (12) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are                as defined above,            -   (13) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are                as defined above,            -   (14) —SO₂—(C₁-C₄ alkyl), or            -   (15) ═O, with the proviso that when n₁ is zero                R_(1-heterocycle) is not bonded to the carbon chain by                nitrogen; or    -   (IX) G-L-A-W-    -   where A is:        -   (I) phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl,            dihydronaphthalyl, tetralinyl, cyclopentyl, cyclohexyl, and            cycloheptyl optionally substituted with one or two of the            following substituents on the ring:        -   (A) —NO₂,        -   (B) —C≡N,        -   (C) —N(R)CO(R′) R, R′defined below        -   (D) —CO—O—R_(N-5) where R_(N-5) is selected from the group            consisting of:            -   (a) C₁-C₆ alkyl, and            -   (b) —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as                defined above,        -   (E) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,        -   (F) —O—(C₂-C₆ alkyl)-COOH,        -   (G) —NRR′ where R, R′ are H, C₁-C₆ alkyl,            —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as defined above,        -   (H) —SR where R is H, C₁-C₆ alkyl, —(CH₂)₀₋₂—(R_(1-aryl))            where R_(1-aryl) is as defined above,        -   (I) —CH₂OH,        -   (J) —CO—(C₁-C₆) alkyl,        -   (K) —CONRR′ where R, R′ are H, C₁-C₆ alkl,            —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as defined above,        -   (L) —SO₂NRR′ where R, R′ are H, C₁-C₆ alkyl,        -   (M) —COOH,        -   (N) —C₁-C₆ alkyl,        -   (O) —C₂-C₆ alkenyl with one or two double bonds, or        -   (P) —C₂-C₆ alkynyl with one or two triple bonds,        -   wherein each of (N), (O) and (P) may be optionally            substituted by one to three of —CF₃, —F, —Cl, —Br, —I, C₁-C₃            alkyoxy, —OCF₃, —NH₂, —OH, and —CN, and provided that G, L            and W may not all be absent;        -   (II) R_(1-heteroaryl) as defined above, where the            R_(1-heteroaryl) group bonds to the subsistent W by a ring            carbon atom, and where R_(1-heteroaryl) is optionally            substituted with one, two, three, or four substituents            independently chosen from the group consisting of:        -   (A) —NO₂,        -   (B) —C≡N,        -   (C) —N(R)CO(R′) where R, R′ are defined below,        -   (D) —CO—O—R_(N-5) where R_(N-5) is selected from the group            consisting of:            -   (a) C₁-C₆ alkyl, and            -   (b) —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as                defined above,        -   (E) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,        -   (F) —O—(C₂-C₆ alkyl)-COOH,        -   (G) —NRR′ where R, R′ are independently H, C₁-C₆ alkyl, and            —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as defined above,        -   (H) —SR where R and R_(1-aryl) are as defined above,        -   (I) —CH₂OH,        -   (J) —CO—(C₁-C₆) alkyl,        -   (K) —CONRR′ where R, R′ and R_(1-aryl) are as defined above,        -   (L) —SO₂NRR′ where R, R′ are H, C₁-C₆ alkyl,        -   (M) —COOH,        -   (N) —C₁-C₆ alkyl,        -   (O) —C₂-C₆ alkenyl with one or two double bonds, and        -   (P) —C₂-C₆ alkynyl with one or two triple bonds,        -   wherein each of (N), (O) and (P) may be optionally            substituted by one to three substituent indepedendly chosen            from the group consisting of —CF₃, —F, —Cl, —Br, —I, C₁-C₃            alkyoxy, —OCF₃, —NH₂, —OH, and —CN, and provided that G, L            and W may not all be absent, or        -   (III) R_(1-heterocycle) as defined above:        -    where the R_(1-heterocycle) group bonds to the subsistent W            by a ring carbon atom, and where R_(1-heteroaryl) is            optionally substituted with one to two substituents            independently chosen from the group consisting of        -   (1) ═O,        -   (2) C₁-C₃ alkyl,        -   (3) —CF₃,        -   (4) —F, Cl, —Br or —I,        -   (5) C₁-C₃ alkoxy,        -   (6) —O—CF₃,        -   (7) —NH₂,        -   (8) —OH, and        -   (9) —C≡N,

and provided that G, L and W may not all be absent,

where W is —S(O)₀₋₂—, —O—, —N—, or absent, and N is optionallysubstituted with C₁-C₄ alkyl;

where L is —CO—, —S(O)₁₋₂—, —O—, —C(Ra)(Rb)O—, —OC(Ra)(Rb)—, —N(Ra)—,—CON(Ra)—, —N(Ra)CO—, —C(Ra)(Rb)—, —C(OH)Ra—, —SO₂NRa—, —N(Ra)SO₂—,—N(Ra)CON(Rb)—, N(Ra)CSN(Rb)—, —OCOO—, —NCOO—, OCON(Ra)—, a bond, or Lis absent when G is absent, and where Ra and Rb are independently H,C₁-C₄ alkyl which are optionally substituted. with OH, C₁-C₄ alkoxy, andup to five —F;

-   -   where G is:    -   (I) —C₁-C₁₀ alkyl optionally substituted with one substituent        selected from the group consisting of:        -   (A) —COOH,        -   (B) —CO—O—(C₁-C₄ alkyl),        -   (C) C₁-C₆ alkoxy,        -   (D) —OH,        -   (E) —NH₂,        -   (F) —C₁-C₆ alkyl optionally substituted with one to five —F        -   (G) —(C₁-C₁₀ alkyl)-O—(C₁-C₃ alkyl),        -   (H) —C₂-C₁₀ alkenyl with one or two double bonds,        -   (I) —C₂-C₁₀ alkynyl with one or two triple bonds,        -   (J) —C₄-C₁₀ hydrocarbyl chain with one double bond and one            triple bond,        -   (K) —R_(1-aryl) where R_(1-aryl) is as defined above,        -   (L) —R_(1-heteroaryl) where R_(1-heteroaryl) is as defined            above,    -   (II) —(CH₂)₀₋₃—(C₃-C₇) cycloalkyl where cycloalkyl can be        optionally substituted with one, two or three substituents        selected from the group consisting of:        -   (A) —COOH,        -   (B) —CO—O—(C₁-C₄ alkyl),        -   (C) C₁-C₆ alkoxy,        -   (D) —OH,        -   (E) —NH₂,        -   (F) —C₁-C₆ alkyl optionally substituted with one to five —F        -   (G) —(C₁-C₁₀ alkyl)-O—(C₁-C₃ alkyl),        -   (H) —C₂-C₁₀ alkenyl with one or two double bonds,        -   (I) —C₂-C₁₀ alkynyl with one or two triple bonds,        -   (J) —C₄-C₁₀ hydrocarbyl chain with one double bond and one            triple bond,        -   (K) —R_(1-aryl) where R_(1-aryl) is as defined above,        -   (L) —R_(1-heteroaryl) where R_(1-heteroaryl) is as defined            above,    -   (III) —(CR′R″)₀₋₄—R_(1-aryl) where R′, R″ and R_(1-aryl) are as        defined above,    -   (IV) —(CH₂)₀₋₄—R_(1-heteroaryl) where R_(1-heteroaryl) is as        defined above,    -   (V) —(CH₂)₀₋₄—R_(1-heterocycle) where R_(1-heterocycle) is as        defined above,    -   (VI) —C(R_(C-1))(R_(C-2))—CO—NH—R_(C-3) where R_(C-1) and        R_(C-2) are independently selected from the group consisting of:        -   (A) —H,        -   (B) —C₁-C₆ alkyl,        -   (C) —(C₀-C₄ alkyl)-R_(1-aryl), wherein R_(1-aryl) is as            defined above,        -   (D) —(C₀-C₄ alkyl)-R_(1-heteroaryl), wherein            R_(1-heteroaryl) is as defined above,        -   (E) —(C₀-C₄ alkyl)-R_(1-heterocycle), wherein            R_(1-heterocycle) is as defined above,        -   (F) —(CH₂)₁₋₄—OH,        -   (G) —(CH₂)₁₋₄—R_(C-4)—(CH₂)₁₋₄—R_(C′-aryl) where R_(C-4) is            —O—, —S— or        -   (H) —NR_(C-5)— where R_(C-5) is — or C₁-C₆ alkyl, and where            R_(C′-aryl) is defined above, and        -   (I) —(CH₂)₁₋₄—R_(C-4)—(CH₂)₁₋₄—R_(C-heteroaryl)where R_(C-4)            and R_(C-heteroaryl) are as defined above,        -   wherein in (C), (D) and (E) C₀ is merely a bond,and where            R_(C-3) is:            -   (a) —H,            -   (b) —C₁-C₆ alkyl,            -   (c) —(C₀-C₄ alkyl)-R_(1-aryl) where R_(1-aryl) is as                defined above,            -   (d) —(C₀-C₄ alkyl)-R_(1-heteroaryl) where                R_(1-heteroaryl) is as defined above,            -   (e) —(C₀-C₄ allyl)-R_(1-heterocycle) where                R_(1-heterocycle) is as defined above,    -   (VII) -cyclopentyl or -cyclohexyl ring fused to a phenyl or        heteroaryl ring where heteroaryl is as defined above and phenyl        and heteroaryl are optionally substituted with one, two or three        of:        -   (A) C₁-C₆ alkyl,        -   (B) —CF₃,        -   (C) —F, Cl, —Br and —I,        -   (D) C₁-C₃ alkoxy,        -   (E) —OCF₃,        -   (F) —NH₂,        -   (G) —OH,        -   (H) —C≡N,        -   (I) —NO₂        -   (J) —CO—OH,        -   (K) —CO—O—R_(N-5) where R_(N-5) is selected from the group            consisting of:            -   (a) C₁-C₆ alkyl, and            -   (b) —(C₀-C₂ aryl)-(R_(1-aryl)) where R_(1-aryl) is as                defined above,        -   (L) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,        -   (M) —O—(C₂-C₅ alkyl)-COOH, or        -   (N) —OR where R is as defined above,        -   (O) —NR—R′ where R and R′ are as defined above,        -   (P) —SR where R is as defined above,        -   (Q) —CF₃,        -   (R) —OCF₃,        -   (S) —N(R)COR′ where R, R′ are as defined above,        -   (T) —NRR′ where R, R′ are as defined above,        -   (U) —SR where R is as defined above,        -   (V) —CH₂OH,        -   (W) —CO—(C₁-C₆) alkyl,        -   (X) —CONRR′ where R, R′ are as defined above, or        -   (Y) —SO₂NRR′ where R is as defined above, or    -   (VIII) —(CH₂)₂—O—(CH₂)₂—OH; wherein R₂ is selected from the        group consisting of:    -   (I) —H,    -   (II) C₁-C₆ alkyl, optionally substituted with one, two or three        substituents selected from the group consisting of C₁-C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (III) —(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is R_(1-aryl) or        R_(1-heteroaryl) where R_(1-aryl) and R_(1-heteroaryl) are as        defined above;    -   (IV) C₂-C₆ alkenyl with one or two double bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl,    -   (V) C₂-C₆ alkynyl with one or two triple bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl, and    -   (VI) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with        one, two or three substituents selected from the group        consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆        alkyl; wherein R₃ is selected from the group consisting of:    -   (I) —H,    -   (II) C₁-C₆ alkyl, optionally substituted with one, two or three        substituents selected from the group consisting of C₁-C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (III) —(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is R_(1-aryl) or        R_(1-heteroaryl) where R_(1-aryl) and R_(1-heteroaryl) are as        defined above;    -   (IV) C₂-C₆ alkenyl with one or two double bonds,    -   (V) C₂-C₆ alkynyl with one or two triple bonds, and    -   (VI) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with        one, two or three substituents selected from the group        consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆        alkyl,        and where R₂ and R₃ are taken together with the carbon to which        they are attached to form a carbocycle of three, four, five, six        and seven carbon atoms, optionally where one carbon atom is        replaced by a heteroatom selected from the group consisting of        —O—, —S—, —SO₂—, —NR_(N-2)—, where R_(N-2) is as defined below;        and

-   wherein R_(C) is selected from the group consisting of C₁-C₁₀ alkyl    optionally substituted with 1, 2, or 3 groups independently selected    from the group consisting of R₂₀₅, —OC═O NR₂₃₅R₂₄₀, —S(═O)₀₋₂ R₂₃₅,    —NR₂₃₅C═O NR₂₃₅R₂₄₀, —C═O NR₂₃₅R₂₄₀, and —S(═O)₂ NR₂₃₅R₂₄₀;    —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl wherein the cycloalkyl is optionally    substituted with 1, 2, or 3 groups independently selected from the    group consisting of R₂₀₅, —CO₂H, and —CO₂—(C₁-C₄ alkyl);    —(CR₂₄₅R₂₅₀)₀₋₄-aryl; —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl,    —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl; —(CR₂₄₅R₂₅₀)₀₋₄-aryl-heteroaryl;    —(CR₂₄₅R₂₅₀)₀₋₄-aryl-heterocycloalkyl; —(CR₂₄₅R₂₅₀)₀₋₄-aryl-aryl;    —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-aryl;    —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heterocycloalkyl;    —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heteroaryl;    —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-heteroaryl;    —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-heterocycloalkyl;    —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-aryl;    —[C(R₂₅₅)(R₂₆₀)]₁₋₃—CO—N—(R₂₅₅)₂; —CH(aryl)₂; —CH(heteroaryl)₂;    —CH(heterocycloalkyl)₂; —CH(aryl)(heteroaryl); cyclopentyl,    cyclohexyl, or cycloheptyl ring fused to aryl, heteroaryl, or    heterocycloalkyl wherein one carbon of the cyclopentyl, cyclohexyl,    or cycloheptyl is optionally replaced with one or two NH, NR₂₁₅, O,    or S(═O)₀₋₂, and wherein the cyclopentyl, cyclohexyl, or cycloheptyl    group can be optionally substituted with 1 or 2 groups that are    independently R₂₀₅, ═O, —CO—NR₂₃₅R₂₄₀, or —SO₂—(C₁-C₄ alkyl); C₂-C₁₀    alkenyl optionally substituted with 1, 2, or 3 R₂₀₅ groups; C₂-C₁₀    alkynyl optionally substituted with 1, 2, or 3 R₂₀₅ groups;    —(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH)—(CH₂)₀₋₁-heteroaryl;    —(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH—(CH₂)₀₋₁-heteroaryl; —CH(-aryl or    -heteroaryl)-CO—O(C₁-C₄ alkyl); —CH(—CH₂—OH)—CH(OH)-phenyl-NO₂;    (C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-OH; —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂; —H;    and —(CH₂)₀₋₆—C(═NR₂₃₅)(NR₂₃₅R₂₄₀); wherein    -   each aryl is optionally substituted with 1, 2, or 3 R₂₀₀;    -   each heteroaryl is optionally substituted with 1, 2, 3, or 4        R₂₀₀;    -   each heterocycloalkyl is optionally substituted with 1, 2, 3, or        4 R₂₁₀;    -   R₂₀₀ at each occurrence is independently selected from the group        consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3        R₂₀₅ groups; OH; —NO₂; halogen; —CO₂H; C≡N;        —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl);        —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl); —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl);        —(CH₂)₀₋₄—CO—(C₃-C₇ cycloalkyl); —(CH₂)₀₋₄—CO-aryl;        —(CH₂)₀₋₄—CO-heteroaryl; —(CH₂)₀₋₄—CO-heterocycloalkyl;        —(CH₂)₀₋₄—CO—O—R₂₁₅; —(CH₂)₀₋₄—SO₂—NR₂₂₀R₂₂₅;        —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl); —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl);        —(CH₂)₀₋₄—SO₂—(C₃-C₇ cycloalkyl); —(CH₂)₀₋₄—N(H or        R₂₁₅)—CO—O—R₂₁₅; —(CH₂)₀₋₄—N(H or R₂₁₅)—CO—N(R₂₁₅)₂;        —(CH₂)₀₋₄—N—CS—N(R₂₁₅)₂; —(CH₂)₀₋₄—N(—H or R₂₁₅)—CO—R₂₂₀;        —(CH₂)₀₋₄—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl);        —(CH₂)₀₋₄—O—P(O)—(OR₂₄₀)₂; —(CH₂)₀₋₄—O—CO—N(R₂₁₅)₂;        —(CH₂)₀₋₄—O—CS—N(R₂₁₅)₂; —(CH₂)₀₋₄—O—(R₂₁₅);        —(CH₂)₀₋₄—O—(R₂₁₅)—COOH; —(CH₂)₀₋₄—S—(R₂₁₅); —(CH₂)₀₋₄—O—(C₁-C₆        alkyl optionally substituted with 1, 2, 3, or 5-F); C₃-C₇        cycloalkyl; C₂-C₆ alkenyl optionally substituted with 1 or 2        R₂₀₅ groups; C₂-C₆ alkynyl optionally substituted with 1 or 2        R₂₀₅ groups; —(CH₂)₀₋₄—N(H or R₂₁₅)—SO₂—R₂₂₀; and        —(CH₂)₀₋₄—C₃-C₇ cycloalkyl;        -   wherein each aryl group at each occurrence is optionally            substituted with 1, 2, or 3 groups that are independently            R₂₀₅, R₂₁₀ or C₁-C₆ alkyl substituted with 1, 2, or 3 groups            that are independently R₂₀₅ or R₂₁₀;        -   wherein each heterocycloalkyl group at each occurrence is            optionally substituted with 1, 2, or 3 groups that are            independently R₂₁₀;        -   wherein each heteroaryl group at each occurrence is            optionally substituted with 1, 2, or 3 groups that are            independently R₂₀₅, R₂₁₀, or C₁-C₆ alkyl substituted with 1,            2, or 3 groups that are independently R₂₀₅ or R₂₁₀;    -   R₂₀₅ at each occurrence is independently selected from the group        consisting of C₁-C₆ alkyl, halogen, —OH, —O-phenyl, —SH, —C≡N,        —CF₃, C₁-C₆ alkoxy, NH₂, NH(C₁-C₆ alkyl), and N—(C₁-C₆        alkyl)(C₁-C₆ alkyl);    -   R₂₁₀ at each occurrence is independently selected from the group        consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3        R₂₀₅ groups; C₂-C₆ alkenyl optionally substituted with 1, 2, or        3 R₂₀₅ groups; C₂-C₆ alkynyl optionally substituted with 1, 2,        or 3 R₂₀₅ groups; halogen; C₁-C₆ alkoxy, C₁-C₆ haloalkoxy;        —NR₂₂₀R₂₂₅; OH; C≡N; C₃-C₇ cycloalkyl optionally substituted        with 1, 2, or 3 R₂₀₅ groups; —CO—(C₁-C₄ alkyl); —SO₂NR₂₃₅R₂₄₀;        —CO—NR₂₃₅R₂₄₀; —SO₂—(C₁-C₄ alkyl); and ═O;    -   R₂₁₅ at each occurrence is independently selected from the group        consisting of C₁-C₆ alkyl, —(CH₂)₀₋₂-(aryl), C₂-C₆ alkenyl,        C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, and —(CH₂)₀₋₂-(heteroaryl),        —(CH₂)₀₋₂-(heterocycloalkyl); wherein the aryl group at each        occurrence is optionally substituted with 1, 2, or 3 groups that        are independently R₂₀₅ or R₂₁₀; wherein the heterocycloalkyl        group at each occurrence is optionally substituted with 1, 2, or        3 R₂₁₀; wherein each heteroaryl group at each occurrence is        optionally substituted with 1, 2, or 3 R₂₁₀;        -   R₂₂₀ and R₂₂₅ at each occurrence are independently selected            from the group consisting of —H, —C₁-C₆ alkyl, hydroxy C₁-C₆            alkyl, amino C₁-C₆ alkyl; halo C₁-C₆ alkyl; —C₃-C₇            cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), —(C₁-C₆            alkyl)-O—(C₁-C₃ alkyl), —C₂-C₆ alkenyl, —C₂-C₆ alkynyl,            —C₁-C₆ alkyl chain with one double bond and one triple bond,            -aryl, -heteroaryl, and -heterocycloalkyl;            -   wherein the aryl group at each occurrence is optionally                substituted with 1, 2, or 3 groups that are                independently R₂₀₅ or R₂₁₀;            -   wherein the heterocycloalkyl group at each occurrence is                optionally substituted with 1, 2, or 3 R₂₁₀;            -   wherein each heteroaryl group at each occurrence is                optionally substituted with 1, 2, or 3 R₂₁₀;    -   R₂₃₅ and R₂₄₀ at each occurrence are independently H, or C₁-C₆        alkyl;    -   R₂₄₅ and R₂₅₀ at each occurrence are independently selected from        the group consisting of H, C₁-C₄ alkyl, C₁-C₄ alkylaryl, C₁-C₄        alkylheteroaryl, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄        haloalkoxy, —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, and phenyl; or    -   R₂₄₅ and R₂₅₀ are taken together with the carbon to which they        are attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon        atoms, optionally where one carbon atom is replaced by a        heteroatom selected from the group consisting of —O—, —S—,        —SO₂—, and —NR₂₂₀—;    -   R₂₅₅ and R₂₆₀ at each occurrence are independently selected from        the group consisting of H; C₁-C₆ alkyl optionally substituted        with 1, 2, or 3 R₂₀₅ groups; C₂-C₆ alkenyl optionally        substituted with 1, 2, or 3 R₂₀₅ groups; C₂-C₆ alkynyl        optionally substituted with 1, 2, or 3 R₂₀₅ groups;        —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl); —(CH₂)₀₋₄—C₃-C₇ cycloalkyl        optionally substituted with 1, 2, or 3 R₂₀₅ groups; —(C₁-C₄        alkyl)-aryl; —(C₁-C₄ alkyl)-heteroaryl; —(C₁-C₄        alkyl)-heterocycloalkyl; -aryl; -heteroaryl; -heterocycloalkyl;        —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-aryl;        —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heteroaryl; and;        —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heterocycloalkyl; wherein        -   R₂₆₅ at each occurrence is independently —O—, —S— or            —N(C₁-C₆ alkyl)-;        -   each aryl or phenyl is optionally substituted with 1, 2, or            3 groups that are independently R₂₀₅, R₂₁₀, or C₁-C₆ alkyl            substituted with 1, 2, or 3 groups that are independently            R₂₀₅ or R₂₁₀;        -   each heteroaryl is optionally substituted with 1, 2, 3, or 4            R₂₀₀,        -   each heterocycloalkyl is optionally substituted with 1, 2,            3, or 4 R₂₁₀.

The invention also provides a method for making a compound of formula(I)

or a pharmaceutically acceptable salt or ester thereof, wherein B, R₂₀,R₂, R₃, n and R_(c) are as defined above or below.

The invention also includes a method of treating a patient who has, orin preventing a patient from getting, a disease or condition selectedfrom the group consisting of Alzheimer's disease, for helping prevent ordelay the onset of Alzheimer's disease, for treating patients with mildcognitive impairment (MCI) and preventing or delaying the onset ofAlzheimer's disease in those who would progress from MCI to AD, fortreating Down's syndrome, for treating humans who have HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treatingcerebral amyloid angiopathy and preventing its potential consequences,i.e. single and recurrent lobar hemorrhages, for treating otherdegenerative dementias, including dementias of mixed vascular anddegenerative origin, dementia associated with Parkinson's disease,dementia associated with progressive supranuclear palsy, dementiaassociated with cortical basal degeneration, or diffuse Lewy body typeof Alzheimer's disease and who is in need of such treatment whichcomprises administration of a therapeutically effective amount of acompound of formula (I), where B, R₂₀, n, R₁, R₂, R₃, and R_(c) are asdefined herein, or pharmaceutically acceptable salts and esters thereof

The invention also includes methods for inhibiting beta-secretaseactivity, for inhibiting cleavage of amyloid precursor protein (APP), ina reaction mixture, at a site between Met596 and Asp597, numbered forthe APP-695 amino acid isotype; or at a corresponding site of an isotypeor mutant thereof, for inhibiting production of amyloid beta peptide (Abeta) in a cell, for inhibiting the production of beta-amyloid plaque inan animal, and for treating or preventing a disease characterized bybeta-amyloid deposits in the brain which comprise administration of atherapeutically effective amount of a compound of formula (I), where B,R₂₀, n, R₁, R₂, R₃, and R_(C) are as defined herein, or pharmaceuticallyacceptable salts and esters thereof

The invention also includes a pharmaceutical composition that comprisesa compound of formula (I), where B, R₂₀, n, R₁, R₂, R₃, and R_(C) are asdefined herein, or pharmaceutically acceptable salts and esters thereof,and one or more pharmaceutically acceptable inert carriers.

The invention also includes the use of a substituted aminoalcohol offormula (I), where B, R₂₀, n, R₁, R₂, R₃, and R_(C) are as definedherein, or pharmaceutically acceptable salts and esters thereof, for themanufacture of a medicament for use in treating a patient who has, or inpreventing a patient from getting, a disease or condition selected fromthe group consisting of Alzheimer's disease, for helping prevent ordelay the onset of Alzheimer's disease, for treating patients with mildcognitive impairment (MCI) and preventing or delaying the onset ofAlzheimer's disease in those who would progress from MCI to AD, fortreating Down's syndrome, for treating humans who have HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treatingcerebral amyloid angiopathy and preventing its potential consequences,i.e. single and recurrent lobar hemorrhages, for treating otherdegenerative dementias, including dementias of mixed vascular anddegenerative origin, dementia associated with Parkinson's disease,dementia associated with progressive supranuclear palsy, dementiaassociated with cortical basal degeneration, diffuse Lewy body type ofAlzheimer's disease and who is in need of such treatment.

The invention provides compounds, compositions, kits, and methods forinhibiting beta-secretase-mediated cleavage of amyloid precursor protein(APP). More particularly, the compounds, compositions, and methods ofthe invention are effective to inhibit the production of A beta peptideand to treat or prevent any human or veterinary disease or conditionassociated with a pathological form of A beta peptide.

The compounds, compositions, and methods of the invention are useful fortreating humans who have Alzheimer's Disease (AD), for helping preventor delay the onset of AD, for treating patients with mild cognitiveimpairment (MCI), and preventing or delaying the onset of AD in thosepatients who would otherwise be expected to progress from MCI to AD, fortreating Down's syndrome, for treating Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch Type, for treating cerebral beta-amyloidangiopathy and preventing its potential consequences such as single andrecurrent lobar hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, fortreating dementia associated with Parkinson's disease, dementiaassociated with progressive supranuclear palsy, dementia associated withcortical basal degeneration, and diffuse Lewy body type AD.

The invention also provides intermediates and methods useful forpreparing the compounds of Formula I.

The compounds of the invention possess beta-secretase inhibitoryactivity. The inhibitory activities of the compounds of the inventionare readily demonstrated, for example, using one or more of the assaysdescribed herein or known in the art.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, a broad aspect of the invention is directed to compoundsof (I), or pharmaceutically acceptable salts or esters thereof, whereinwhere B, R₂₀, n, R₁, R₂, R₃, and R_(C) are as defined as above.

In a preferred embodiment, R₁ is G-L-A-E-W-, wherein

E is a bond or C₁-C₃ alkylene;

A is:

-   -   (I) aryl or cycloalkyl where each aryl or cycloalkyl is        optionally substituted with one, two or three independently        selected R₁₀₀ groups, where R₁₀₀ is        -   (A) —NO₂,        -   (B) —C≡N,        -   (C) —N(R)CO(R′)R, where R and R′ are independently hydrogen,            C₁-C₆ alkyl, or —(CH₂)₀₋₂-aryl or —(CH₂)₀₋₂-cycloalkyl,            where each aryl or cycloalkyl is optionally substituted with            halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkyl, amino,            mono(C₁-C₆)alkylamino, or di(C₁-C₆)alkylamino,        -   (D) —CO₂—R₂₅, where R₂₅ is selected from the group            consisting of:            -   (a) C₁-C₆ alkyl,            -   (b) —(CH₂)₀₋₂-cycloalkyl,            -   (c) —(CH₂)₀₋₂-aryl, where the aryl is optionally                substituted with halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆                alkyl, amino, mono(C₁-C₆)alkylamino, or                di(C₁-C₆)alkylamino, and            -   (d) hydrogen,        -   (E) —NH—CO₂—R₂₅,        -   (F) —O—(C₂-C₆ alkyl)-CO₂H,        -   (G) —NRR′,        -   (H) —SR,        -   (I) —CH₂OH,        -   (J) —C(O)—(C₁-C₆)alkyl,        -   (K) —C(O)NRR′,        -   (L) —SO₂NRR′        -   (M) —CO₂H,        -   (N) C₁-C₆ alkyl, C₁-C₆ alkenyl with one or two double bonds,            —C₁-C₆ alkynyl with one or two triple bonds, —CF₃, —F, —Cl,            —Br, —I, C₁-C₃ alkoxy, —OCF₃, —NH₂, —OH, or —CN,        -   (O) halogen, and        -   (P) —(CH₂)₀₋₂—O—(CH₂)₀₋₂—OH;    -   (II) heteroaryl, provided that, when E is a bond, the heteroaryl        group is bonded through one of its carbon atoms to W, and where        the heteroaryl is optionally substituted with one or two        independently selected R₁₀₀ groups;    -   (III) heterocycle, provided that, when E is a bond, the        heterocycle group is bonded through one of its carbon atoms to        W, where the heterocycle is optionally substituted with one or        two independently selected R₂₀₀ groups, where R₂₀₀ is        -   (1) ═O,        -   (2) C₁-C₃ alkyl,        -   (3) —CF₃,        -   (4) —F, Cl, —Br and —I,        -   (5) C₁-C₃ alkoxy,        -   (6) —OCF₃,        -   (7) —NH₂,        -   (8) —OH, or        -   (9) —C≡N;

W is a bond, —S—, —S(O)—, —SO₂—, —O—, —N(R)— where R is hydrogen orC₁-C₄ alkyl;

L is a bond or absent when G is absent, or L is —(O)—, —S(O)—, —SO₂—,—O—, —C(R₁₁₀)(R₁₁₂)O—, —OC(R₁₁₀)(R₁₁₂)—, —N(R₁₁₀)—, —CON(R₁₁₀)—,—N(R₁₁₀)CO—, —C(R₁₁₀)(R′)—, —C(OH)R₁₁₀—, —SO₂NR₁₁₀—, —N(R₁₁₀)SO₂—,—N(R₁₁₀)CON(R₁₁₂)—, N(R₁₁₀)CSN(R₁₁₂)—, —OCO₂—, —NCO₂—, or —OCON(R₁₁₀)—,where R₁₁₀ and R₁₁₂ are independently hydrogen, or C₁-C₄ alkyl, whereC₁-C₄ alkyl is optionally substituted with OH, C₁-C₄ alkoxy, or one tofive F;

G is absent or:

-   -   (I) C₁-C₁₀ alkyl, optionally substituted with up to three groups        independently selected from        -   (A) —CO₂H,        -   (B) —CO₂(C₁-C₄ alkyl),        -   (C) C₁-C₆ alkoxy,        -   (D) —OH,        -   (E) —NRR′,        -   (F) —C₁-C₆ haloalkyl,        -   (G) —(C₁-C₁₀alkyl)-O—(C₁-C₃ alkyl),        -   (H) —C₁-C₁₀ alkenyl with one or two double bonds,        -   (I) —C₁-C₁₀ alkynyl with one or two triple bonds,        -   (J) —C₁-C₁₀ alkyl chain with one double bond and one triple            bond,        -   (K) aryl optionally substituted with R₁₀₀,        -   (L) heteroaryl optionally substituted with R₁₀₀,        -   (M) C₁-C₆ alkyl,    -   (II) —(CH₂)₀₋₃—(C₃-C₇) cycloalkyl where cycloalkyl is optionally        substituted with one, two or three substituents selected from        the group consisting of:        -   (A) —CO₂H,        -   (B) —CO₂—(C₁-C₄ alkyl),        -   (C) C₁-C₆ alkoxy,        -   (D) —OH,        -   (E) —NH₂,        -   (F) —C₁-C₆ haloalkyl,        -   (G) —(C₁-C₁₀ alkyl)-O—(C₁-C₃ alkyl),        -   (H) —C₁-C₁₀ alkenyl with one or two double bonds,        -   (I) —C₁-C₁₀ alkynyl with one or two triple bonds,        -   (J) —C₁-C₁₀ alkyl chain with one double bond and one triple            bond,        -   (K) aryl optionally substituted with R₁₀₀,        -   (L) heteroaryl optionally substituted with R₁₀₀,        -   (m) mono(C₁-C₆ alkyl)amino, and        -   (n) di(C₁-C₆ alkyl) amino,        -   (o) C₁-C₆ alkyl,    -   (III) —(CRR)₀₋₄-aryl where aryl is optionally substituted with        R₁₀₀,    -   (IV) —(CH₂)₀₋₄-heteroaryl where the heteroaryl is optionally        substituted with one, two, or three independently selected R₁₀₀        groups,    -   (V) —(CH₂)₀₋₄-heterocycle, where the heterocycle is optionally        substituted with one or two R₂₀₀ groups,    -   (VI) —C(R₁₀)(R₁₂)—CO—NH-R₁₄ where        -   R₁₀ and R₁₂ are the same or different and are selected from            the group consisting of:        -   (A) —H,        -   (B) —C₁-C₆ alkyl,        -   (C) —(C₁-C₄ alkyl)-aryl, where the aryl is optionally            substituted with one, two, or three independently selected            R₁₀₀ groups,        -   (D) —(C₁-C₄ alkyl)-heteroaryl where the heteroaryl is            optionally substituted with one, two, or three independently            selected R₁₀₀ groups,        -   (E) —(C₁-C₄ alkyl)-heterocycle, where the heterocycle is            optionally substituted with one or two R₂₀₀ groups,        -   (F) heteroaryl where the heteroaryl is optionally            substituted with one, two, or three independently selected            R₁₀₀ groups,        -   (G) heterocycle, where the heterocycle is optionally            substituted with one or two R₂₀₀ groups,        -   (H) —(CH₂)₁₋₄—OH,        -   (I) —(CH₂)₁₋₄—Y—(CH₂)₁₋₄-aryl where Y is —O—, —S— or            —NR_(C-5)— where R₁₆ is hydrogen or C₁-C₆ alkyl, and where            the aryl is optionally substituted with one, two, or three            independently selected R₁₀₀ groups,        -   (J) —(CH₂)₁₋₄—Y—(CH₂)₁₋₄-heteroaryl where the heteroaryl is            optionally substituted with one, two, or three independently            selected R₁₀₀ groups, and        -   (K) -aryl, where the aryl is optionally substituted with            one, two, or three independently selected R₁₀₀ groups, and        -   R₁₄ is:        -   (A) —H,        -   (B) —C₁-C₆ alkyl,        -   (C) -aryl, where the aryl is optionally substituted with            one, two, or three independently selected R₁₀₀ groups,        -   (D) -heteroaryl where the heteroaryl is optionally            substituted with one, two, or three independently selected            R₁₀₀ groups,        -   (E) -heterocycle, where the heterocycle is optionally            substituted with one or two R₂₀₀ groups,        -   (F) —(C₁-C₄ alkyl)-aryl, where the aryl is optionally            substituted with one, two, or three independently selected            R₁₀₀ groups,        -   (G) —(C₁-C₄ alkyl)-heteroaryl where the heteroaryl is            optionally substituted with one, two, or three independently            selected R₁₀₀ groups,        -   (H) —(C₁-C₄ alkyl)-heterocycle, where the heterocycle is            optionally substituted with one or two R₂₀₀ groups, or        -   (I) —(CH₂)₀₋₂—O—(CH₂)₀₋₂—OH;R₄ and R₅ are independently            hydrogen, halogen, C₁-C₆ alkoxy or C₁-C₄ alkyl.

In another embodiment, R₁ is

-   -   —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl), or    -   C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups        independently selected from halogen, —OH, ═O, —SH, —C≡N, —CF₃,        —C₁-C₃ alkoxy, amino, mono- or dialkylamino, —OC(═O)-amino,        -amino-C(═O)O—, and —OC(═O)-mono- or dialkylamino, or C₁-C₁₀        alkyl optionally substituted —C₁-C₃ alkoxy, or    -   C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionally        substituted with 1, 2, or 3 groups independently selected from        halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or        dialkylamino, or    -   aryl, heteroaryl, heterocyclyl, —C₁-C₆ alkyl-aryl, —C₁-C₆        alkyl-heteroaryl, or —C₁-C₆ alkyl-heterocyclyl, where the ring        portions of each are optionally substituted with 1, 2, 3, or 4        groups independently selected from halogen, —OH, —SH, —C≡N,        —NR₇R′₇, —C(═O)—(C₁-C₄) alkyl, —SO₂-amino, —SO₂-mono or        dialkylamino, —C(═O)-amino, —C(═O)-mono or dialkylamino,        —SO₂—(C₁-C₄) alkyl, or    -   —C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups        which are independently a halogen, or    -   C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groups        independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, amino, —C₁-C₆ alkyl and mono- or dialkylamino, or    -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups        independently selected from halogen, —OH, —SH, —C≡N, —CF₃,        —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, or    -   C₂-C₆ alkenyl, alk(di)enyl, C₂-C₆ alkynyl or alk(di)ynyl, each        of which is optionally substituted with 1, 2, or 3 groups        independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, amino, —C₁-C₆ alkyl and mono- or dialkylamino; and the        heterocyclyl group is optionally further substituted with oxo.

In a preferred embodiment [non-difluorobenzyl embodiment; removal ofmultiple inactive compounds], R₁ is:

-   -   (I) C₁-C₆ alkyl, optionally substituted with one, two or three        substituents selected from the group consisting of C₁-C₃ alkyl,        C₁-C₇ alkyl (optionally substituted with C₁-C₃ alkyl and C₁-C₃        alkoxy), —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆        alkyl, —OC═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as        defined above,    -   (II) —CH₂—S(O)₀₋₂—(C₁-C₆ alkyl),    -   (III) —CH₂—CH₂—S(O)₀₋₂—(C₁-C₆ alkyl),    -   (IV) C₂-C₆ alkenyl with one or two double bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl,    -   (V) C₂-C₆ alkynyl with one or two triple bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl,    -   (VI) —(CH₂)_(n1)—(R_(1-aryl)) where n₁ is zero or one and where        R_(1-aryl) is phenyl, 1-naphthyl, 2-naphthyl and indanyl,        indenyl, dihydronaphthalyl, tetralinyl optionally substituted        with one, two, three or four of the following substituents on        the aryl ring:        -   (A) C₁-C₆ alkyl optionally substituted with one, two or            three substituents selected from the group consisting of            C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b)            where R_(1-a) and R_(1-b) are as defined above, —C≡N, —CF₃,            C₁-C₃ alkoxy,        -   (B) C₂-C₆ alkenyl with one or two double bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁-C₆ alkyl,        -   (C) C₂-C₆ alkynyl with one or two triple bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁-C₆ alkyl,        -   (D) —Cl, —Br and —I,        -   (F) —C₁-C₆ alkoxy optionally substituted with one, two or            three —F,        -   (G) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as            defined below,        -   (H) —OH,        -   (I) —C≡N,        -   (J) C₃-C₇ cycloalkyl, optionally substituted with one, two            or three substituents selected from the group consisting of            —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,            —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆            alkyl,        -   (K) —CO—(C₁-C₄ alkyl),        -   (L) —SO₂—NR_(1-b)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above,        -   (M) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above, or        -   (N) —SO₂—(C₁-C₄ alkyl),    -   (VII) —(CH₂)_(n1)—(R_(1-heteroaryl)) where n₁ is as defined        above and where R_(1-heteroaryl) is selected from the group        consisting of:        -   (A) pyridinyl,        -   (B) pyrimidinyl,        -   (C) quinolinyl,        -   (F) benzothienyl,        -   (G) indolyl,        -   (H) indolinyl,        -   (I) pryidazinyl,        -   (J) pyrazinyl,        -   (K) isoindolyl,        -   (L) isoquinolyl,        -   (M) quinazolinyl,        -   (N) quinoxalinyl        -   (O) phthalazinyl,        -   (P) imidazolyl,        -   (Q) isoxazolyl,        -   (R) pyrazolyl,        -   (S) oxazolyl,        -   (T) thiazolyl,        -   (U) indolizinyl,        -   (V) indazolyl,        -   (W) benzothiazolyl,        -   (X) benzimidazolyl,        -   (Y) benzofuranyl,        -   (Z) furanyl,        -   (AA) thienyl,        -   (BB) pyrrolyl,        -   (CC) oxadiazolyl,        -   (DD) thiadiazolyl,        -   (EE) triazolyl,        -   (FF) tetrazolyl,        -   (II) oxazolopyridinyl,        -   (JJ) imidazopyridinyl,        -   (KK) isothiazolyl,        -   (LL) naphthyridinyl,        -   (MM) cinnolinyl,        -   (NN) carbazolyl,        -   (OO) beta-carbolinyl,        -   (PP) isochromanyl,        -   (QQ) chromanyl,        -   (SS) tetrahydroisoquinolinyl,        -   (TT) isoindolinyl,        -   (UU) isobenzotetrahydrofuranyl,        -   (VV) isobenzotetrahydrothienyl,        -   (WW) isobenzothienyl,        -   (XX) benzoxazolyl,        -   (YY) pyridopyridinyl,        -   (ZZ) benzotetrahydrofuranyl,        -   (AAA) benzotetrahydrothienyl,        -   (BBB) purinyl,        -   (CCC) benzodioxolyl,        -   (DDD) triazinyl,        -   (EEE) phenoxazinyl,        -   (FFF) phenothiazinyl,        -   (GGG) pteridinyl,        -   (HHH) benzothiazolyl,        -   (III) imidazopyridinyl,        -   (JJJ) imidazothiazolyl,        -   (KKK) dihydrobenzisoxazinyl,        -   (LLL) benzisoxazinyl,        -   (MMM) benzoxazinyl,        -   (NNN) dihydrobenzisothiazinyl,        -   (OOO)benzopyranyl,        -   (PPP) benzothiopyranyl,        -   (QQQ) coumarinyl,        -   (RRR) isocoumarinyl,        -   (SSS) chromonyl,        -   (TTT) chromanonyl, and        -   (UUU) pyridinyl-N-oxide,        -    where the R_(1-heteroaryl) group is bonded to —(CH₂)_(n-1)—            by any ring atom of the parent R_(N-heteroaryl) group            substituted by hydrogen such that the new bond to the            R_(1-heteroaryl) group replaces the hydrogen atom and its            bond, where heteroaryl is optionally substituted with one,            two, three or four of:        -   (1) C₁-C₆ alkyl optionally substituted with one, two or            three substituents selected from the group consisting of            C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b)            where R_(1-a) and R_(1-b) are as defined above, —C≡N, —CF₃,            C₁-C₃ alkoxy,        -   (2) C₂-C₆ alkenyl with one or two double bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁-C₆ alkyl,        -   (3) C₂-C₆ alkynyl with one or two triple bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁-C₆ alkyl,        -   (4) —F, Cl, —Br and —I,        -   (6) —C₁-C₆ alkoxy optionally substituted with one, two, or            three —F,        -   (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as            defined below,        -   (8) —OH,        -   (9) —C≡N,        -   (10) C₃-C₇ cycloalkyl, optionally substituted with one, two            or three substituents selected from the group consisting of            —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,            —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆            alkyl,        -   (11) —CO—(C₁-C₄ alkyl),        -   (12) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above,        -   (13) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above, or        -   (14) —SO₂—(C₁-C₄ alkyl), with the proviso that when n₁ is            zero R_(1-heteroaryl) is not bonded to the carbon chain by            nitrogen,    -   (VII) —(CH₂)_(n1)—(R_(1-heterocycle)) where n₁ is as defined        above and R_(1-heterocycle) is selected from the group        consisting of:        -   (A) morpholinyl,        -   (B) thiomorpholinyl,        -   (C) thiomorpholinyl S-oxide,        -   (D) thiomorpholinyl S,S-dioxide,        -   (E) piperazinyl,        -   (F) homopiperazinyl,        -   (G) pyrrolidinyl,        -   (H) pyrrolinyl,        -   (I) tetrahydropyranyl,        -   (J) piperidinyl,        -   (K) tetrahydropyranyl,        -   (L) tetrahydrothienyl,        -   (M) homopiperidinyl,        -   (N) homomorpholinyl,        -   (O) homothiomorpholinyl,        -   (P) homomorpholinyl S-oxide,        -   (Q) homothiomorpholinyl S,S-dioxide, and        -   (R) oxazolidinonyl,        -    where the R_(1-heterocycle) group is bonded by any atom of            the parent R_(1-heterocycle) group substituted by hydrogen            such that the new bond to the R_(1-heterocycle) group            replaces the hydrogen atom and its bond, where heterocycle            is optionally substituted with one, two, three or four of:            -   (1) C₁-C₆ alkyl optionally substituted with one, two or                three substituents selected from the group consisting of                C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,                —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as                defined above, —C≡N, —CF₃, C₁-C₃ alkoxy,            -   (2) C₂-C₆ alkenyl with one or two double bonds,                optionally substituted with one, two or three                substituents selected from the group consisting of —F,                —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,                —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or                C₁-C₆ alkyl,            -   (3) C₂-C₆ alkynyl with one or two triple bonds,                optionally substituted with one, two or three                substituents selected from the group consisting of —F,                —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,                —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or                C₁-C₆ alkyl,            -   (4) —F, Cl, —Br and —I,            -   (5) C₁-C₆ alkoxy,            -   (6) —C₁-C₆ alkoxy optionally substituted with one, two,                or three —F,            -   (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as                defined below,            -   (8) —OH,            -   (9) —C≡N,            -   (10) C₃-C₇ cycloalkyl, optionally substituted with one,                two or three substituents selected from the group                consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃                alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are                —H or C₁-C₆ alkyl,            -   (11) —CO—(C₁-C₄ alkyl),            -   (12) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are                as defined above,            -   (13) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are                as defined above,            -   (14) —SO₂—(C₁-C₄ alkyl), or            -   (15) ═O, with the proviso that when n₁ is zero                R_(1-heterocycle) is not bonded to the carbon chain by                nitrogen; or    -   (IX) G-L-A-W-    -   where A is:        -   (I) phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl,            dihydronaphthalyl, tetralinyl, cyclopentyl, cyclohexyl, and            cycloheptyl optionally substituted with one or two of the            following substituents on the ring:        -   (A) —NO₂,        -   (B) —C≡N,        -   (C) —N(R)CO(R′) R, R′defined below        -   (D) —CO—O—R_(N-5) where R_(N-5) is selected from the group            consisting of:            -   (a) C₁-C₆ alkyl, and            -   (b) —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as                defined above,        -   (E) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,        -   (F) —O—(C₂-C₆ alkyl)-COOH,        -   (G) —NRR′ where R, R′ are H, C₁-C₆ alkyl,            —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as defined above,        -   (H) —SR where R is H, C₁-C₆ alkyl, —(CH₂)₀₋₂—(R_(1-aryl))            where R_(1-aryl) is as defined above,        -   (I) —CH₂OH,        -   (J) —CO—(C₁-C₆) alkyl,        -   (K) —CONRR′ where R, R′ are H, C₁-C₆ alkyl,            —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as defined above,        -   (L) —SO₂NRR′ where R, R′ are H, C₁-C₆ alkyl,        -   (M) —COOH,        -   (N) —C₁-C₆ alkyl,        -   (O) —C₂-C₆ alkenyl with one or two double bonds, or        -   (P) —C₂-C₆ alkynyl with one or two triple bonds,        -   wherein each of (N), (O) and (P) may be optionally            substituted by one to three of —CF₃, —F, —Cl, —Br, —I, C₁-C₃            alkyoxy, —OCF₃, —NH₂, —OH, and —CN, and provided that G, L            and W may not all be absent;        -   (II) R_(1-heteroaryl) as defined above, where the            R_(1-heteroaryl) group bonds to the subsistent W by a ring            carbon atom, and where R_(1-heteroaryl) is optionally            substituted with one, two, three, or four substituents            independently chosen from the group consisting of:        -   (A) —NO₂,        -   (B) —C≡N,        -   (C) —N(R)CO(R′) where R, R′ are defined below,        -   (D) —CO—O—R_(N-5) where R_(N-5) is selected from the group            consisting of:            -   (a) C₁-C₆ alkyl, and            -   (b) —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as                defined above,        -   (E) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,        -   (F) —O—(C₂-C₆ alkyl)-COOH,        -   (G) —NRR′ where R, R′ are independently H, C₁-C₆ alkyl, and            —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as defined above,        -   (H) —SR where R and R_(1-aryl) are as defined above,        -   (I) —CH₂OH,        -   (J) —CO—(C₁-C₆) alkyl,        -   (K) —CONRR′ where R, R′ and R_(1-aryl) are as defined above,        -   (L) —SO₂NRR′ where R, R′ are H, C₁-C₆ alkyl,        -   (M) —COOH,        -   (N) —C₁-C₆ alkyl,        -   (O) —C₂-C₆ alkenyl with one or two double bonds, and        -   (P) —C₂-C₆ alkynyl with one or two triple bonds,        -   wherein each of (N), (O) and (P) may be optionally            substituted by one to three substituent indepedendly chosen            from the group consisting of —CF₃, —F, —Cl, —Br, —I, C₁-C₃            alkyoxy, —OCF₃, —NH₂, —OH, and —CN, and provided that G, L            and W may not all be absent, or        -   (III) R_(1-heterocycle) as defined above:    -   where the R_(1-heterocycle) group bonds to the subsistent W by a        ring carbon atom, and where R_(1-heteroaryl) is optionally        substituted with one to two substituents independently chosen        from the group consisting of        -   (1) ═O,        -   (2) C₁-C₃ alkyl,        -   (3) —CF₃,        -   (4) —F, Cl, —Br or —I,        -   (5) C₁-C₃ alkoxy,        -   (6) —O—CF₃,        -   (7) —NH₂,        -   (8) —OH, and        -   (9) —C≡N,

and provided that G, L and W may not all be absent,

where W is —S(O)₀₋₂—, —O—, —N—, or absent, and N is optionallysubstituted with C₁-C₄ alkyl;

where L is —CO—, —S(O)₁₋₂—, —O—, —C(Ra)(Rb)O—, —OC(Ra)(Rb)—, —N(Ra)—,—CON(Ra)—, —N(Ra)CO—, —C(Ra)(Rb)—, —C(OH)Ra—, —SO₂NRa—, —N(Ra)SO₂—,—N(Ra)CON(Rb)—, N(Ra)CSN(Rb)—, —OCOO—, —NCOO—, OCON(Ra)—, a bond, or Lis absent when G is absent, and where Ra and Rb are independently H,C₁-C₄ alkyl which are optionally substituted. with OH, C₁-C₄ alkoxy, andup to five —F;

-   -   where G is:    -   (I) —C₁-C₁₀ alkyl optionally substituted with one substituent        selected from the group consisting of:        -   (A) —COOH,        -   (B) —CO—O—(C₁-C₄ alkyl),        -   (C) C₁-C₆ alkoxy,        -   (D) —OH,        -   (E) —NH₂,        -   (F) —C₁-C₆ alkyl optionally substituted with one to five —F        -   (G) —(C₁-C₁₀ alkyl)-O—(C₁-C₃ alkyl),        -   (H) —C₂-C₁₀ alkenyl with one or two double bonds,        -   (I) —C₂-C₁₀ alkynyl with one or two triple bonds,        -   (J) —C₄-C₁₀ hydrocarbyl chain with one double bond and one            triple bond,        -   (K) —R_(1-aryl) where R_(1-aryl) is as defined above,        -   (L) —R_(1-heteroaryl) where R_(1-heteroaryl) is as defined            above,    -   (II) —(CH₂)₀₋₃—(C₃-C₇) cycloalkyl where cycloalkyl can be        optionally substituted with one, two or three substituents        selected from the group consisting of:        -   (A) —COOH,        -   (B) —CO—O—(C₁-C₄ alkyl),        -   (C) C₁-C₆ alkoxy,        -   (D) —OH,        -   (E) —NH₂,        -   (F) —C₁-C₆ alkyl optionally substituted with one to five —F        -   (G) —(C₁-C₁₀ alkyl)-O—(C₁-C₃ alkyl),        -   (H) —C₂-C₁₀ alkenyl with one or two double bonds,        -   (I) —C₂-C₁₀ alkynyl with one or two triple bonds,        -   (J) —C₄-C₁₀ hydrocarbyl chain with one double bond and one            triple bond,        -   (K) —R_(1-aryl) where R_(1-aryl) is as defined above,        -   (L) —R_(1-heteroaryl) where R_(1-heteroaryl) is as defined            above,    -   (III) —(CR′R″)₀₋₄—R_(1-aryl) where R′, R″ and R_(1-aryl) are as        defined above,    -   (IV) —(CH₂)₀₋₄—R_(1-heteroaryl) where R_(1-heteroaryl) is as        defined above,    -   (V) —(CH₂)₀₋₄—R_(1-heterocycle) where R_(1-heterocycle) is as        defined above,    -   (VI) —C(R_(C-1))(R_(C-2))—CO—NH—R_(C-3) where R_(C-1) and        R_(C-2) are independently selected from the group consisting of:        -   (A) —H,        -   (B) —C₁-C₆ alkyl,        -   (C) —(C₀-C₄ alkyl)-R_(1-aryl), wherein R_(1-aryl) is as            defined above,        -   (D) —(C₀-C₄ alkyl)-R_(1-heteroaryl), wherein            R_(1-heteroaryl) is as defined above,        -   (E) —(C₀-C₄ alkyl)-R_(1-heterocycle), wherein            R_(1-heterocycle) is as defined above,        -   (F) —(CH₂)₁₋₄—OH,        -   (G) —(CH₂)₁₋₄—R_(C-4)—(CH₂)₁₋₄—R_(C′-aryl) where R_(C-4) is            —O—, —S— or        -   (H) —NR_(C-5)— where R_(C-5) is — or C₁-C₆ alkyl, and where            R_(C′-aryl) is defined above, and        -   (I) —(CH₂)₁₋₄—R_(C-4)—(CH₂)₁₋₄—R_(C-heteroaryl) where            R_(C-4) and R_(C-heteroaryl) are as defined above,        -   wherein in (C), (D) and (E) C₀ is merely a bond,and where            R_(C-3) is:            -   (a) —H,            -   (b) —C₁-C₆ alkyl,            -   (c) —(C₀-C₄ alkyl)-R_(1-aryl) where R_(1-aryl) is as                defined above,            -   (d) —(C₀-C₄ alkyl)-R_(1-heteroaryl) where                R_(1-heteroaryl) is as defined above,            -   (e) —(C₀-C₄ alkyl)-R_(1-heterocycle) where                R_(1-heterocycle) is as defined above,    -   (VII) -cyclopentyl or -cyclohexyl ring fused to a phenyl or        heteroaryl ring where heteroaryl is as defined above and phenyl        and heteroaryl are optionally substituted with one, two or three        of:        -   (B) C₁-C₆ alkyl,        -   (B) —CF₃,        -   (C) —F, Cl, —Br and —I,        -   (D) C₁-C₃ alkoxy,        -   (E) —OCF₃,        -   (F) —NH₂,        -   (G) —OH,        -   (H) —C≡N,        -   (I) —NO₂        -   (J) —CO—OH,        -   (K) —CO—O—R_(N-5) where R_(N-5) is selected from the group            consisting of:            -   (a) C₁-C₆ alkyl, and            -   (b) —(C₀-C₂ alkyl)-(R_(1-aryl)) where R_(1-aryl) is as                defined above,        -   (L) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,        -   (M) —O—(C₂-C₅ alkyl)-COOH, or        -   (N) —OR where R is as defined above,        -   (O) —NR—R′ where R and R′ are as defined above,        -   (P) —SR where R is as defined above,        -   (Q) —CF₃,        -   (R) —OCF₃,        -   (S) —N(R)COR′ where R, R′ are as defined above,        -   (T) —NRR′ where R, R′ are as defined above,        -   (U) —SR where R is as defined above,        -   (V) —CH₂OH,        -   (W) —CO—(C₁-C₆) alkyl,        -   (X) —CONRR′ where R, R′ are as defined above, or        -   (Y) —SO₂NRR′ where R is as defined above, or    -   (VIII) —(CH₂)₂—O—(CH₂)₂—OH.

In yet another preferred embodiment [non-phenyl embodiment; removal ofmultiple inactive compounds], Rc is selected from the group consistingof C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from the group consisting of R₂₀₅, —OC═ONR₂₃₅R₂₄₀, —S(═O)₀₋₂ R₂₃₅, —NR₂₃₅C═O NR₂₃₅R₂₄₀, —C═O NR₂₃₅R₂₄₀, and—S(═O)₂ NR₂₃₅R₂₄₀; —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl wherein the cycloalkylis optionally substituted with 1, 2, or 3 groups independently selectedfrom the group consisting of R₂₀₅, —CO₂H, and —CO₂—(C₁-C₄ alkyl);—(CR₂₄₅R₂₅₀)₁₋₄-aryl; —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl,—(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl; —(CR₂₄₅R₂₅₀)₀₋₄-aryl-heteroaryl;—(CR₂₄₅R₂₅₀)₀₋₄-aryl-heterocycloalkyl; —(CR₂₄₅R₂₅₀)₀₋₄-aryl-aryl;—(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-aryl;—(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heterocycloalkyl;—(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heteroaryl;—(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-heteroaryl;—(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-heterocycloalkyl;—(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-aryl; —[C(R₂₅₅)(R₂₆₀)]₁₋₃—CO—N—(R₂₅₅)₂;—CH(aryl)₂; —CH(heteroaryl)₂; —CH(heterocycloalkyl)₂;—CH(aryl)(heteroaryl); cyclopentyl, cyclohexyl, or cycloheptyl ringfused to aryl, heteroaryl, or heterocycloalkyl wherein one carbon of thecyclopentyl, cyclohexyl, or cycloheptyl is optionally replaced with oneor two NH, NR₂₁₅, O, or S(═O)₀₋₂, and wherein the cyclopentyl,cyclohexyl, or cycloheptyl group can be optionally substituted with 1 or2 groups that are independently R₂₀₅, ═O, —CO—NR₂₃₅R₂₄₀, or —SO₂—(C₁-C₄alkyl); C₂-C₁₀ alkenyl optionally substituted with 1, 2, or 3 R₂₀₅groups; C₂-C₁₀ alkynyl optionally substituted with 1, 2, or 3 R₂₀₅groups; —(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH)—(CH₂)₀₋₁-aryl;—(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH—(CH₂)₀₋₁-heteroaryl; —CH(-aryl or-heteroaryl)-CO—O(C₁-C₄ alkyl); —CH(—CH₂—OH)—CH(OH)-phenyl-NO₂; (C₁-C₆alkyl)-O—(C₁-C₆ alkyl)-OH; —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂; —H; and—(CH₂)₀₋₆—C(═NR₂₃₅)(NR₂₃₅R₂₄₀); wherein

-   each aryl is optionally substituted with 1, 2, or 3 R₂₀₀;-   each heteroaryl is optionally substituted with 1, 2, 3, or 4 R₂₀₀;-   each heterocycloalkyl is optionally substituted with 1, 2, 3, or 4    R₂₁₀;-   R₂₀₀ at each occurrence is independently selected from the group    consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; OH; —NO₂; halogen; —CO₂H; C≡N; —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅;    —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl); —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl);    —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl); —(CH₂)₀₋₄—CO—(C₃-C₇ cycloalkyl);    —(CH₂)₀₋₄—CO-aryl; —(CH₂)₀₋₄—CO-heteroaryl;    —(CH₂)₀₋₄—CO-heterocycloalkyl; —(CH₂)₀₋₄—CO—O—R₂₁₅;    —(CH₂)₀₋₄—SO₂—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl);    —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl); —(CH₂)₀₋₄—SO₂—(C₃-C₇ cycloalkyl);    —(CH₂)₀₋₄—N(H or R₂₁₅)—CO—O—R₂₁₅; —(CH₂)₀₋₄—N(H or    R₂₁₅)—CO—N(R₂₁₅)₂; —(CH₂)₀₋₄—N—CS—N(R₂₁₅)₂; —(CH₂)₀₋₄—N(—H or    R₂₁₅)—CO—R₂₂₀; —(CH₂)₀₋₄—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl);    —(CH₂)₀₋₄—O—P(O)—(OR₂₄₀)₂; —(CH₂)₀₋₄—O—CO—N(R₂₁₅)₂;    —(CH₂)₀₋₄—O—CS—N(R₂₁₅)₂; —(CH₂)₀₋₄—O—(R₂₁₅);    —(CH₂)₀₋₄—O—(R₂₁₅)—COOH; —(CH₂)₀₋₄—S—(R₂₁₅); —(CH₂)₀₋₄—O—(C₁-C₆    alkyl optionally substituted with 1, 2, 3, or 5—F); C₃-C₇    cycloalkyl; C₂-C₆ alkenyl optionally substituted with 1 or 2 R₂₀₅    groups; C₂-C₆ alkynyl optionally substituted with 1 or 2 R₂₀₅    groups; —(CH₂)₀₋₄—N(H or R₂₁₅)—SO₂—R₂₂₀; and —(CH₂)₀₋₄—C₃-C₇    cycloalkyl;    -   wherein each aryl group at each occurrence is optionally        substituted with 1, 2, or 3 groups that are independently R₂₀₅,        R₂₁₀ or C₁-C₆ alkyl substituted with 1, 2, or 3 groups that are        independently R₂₀₅ or R₂₁₀;    -   wherein each heterocycloalkyl group at each occurrence is        optionally substituted with 1, 2, or 3 groups that are        independently R₂₁₀;    -   wherein each heteroaryl group at each occurrence is optionally        substituted with 1, 2, or 3 groups that are independently R₂₀₅,        R₂₁₀, or C₁-C₆ alkyl substituted with 1, 2, or 3 groups that are        independently R₂₀₅ or R₂₁₀;-   R₂₀₅ at each occurrence is independently selected from the group    consisting of C₁-C₆ alkyl, halogen, —OH, —O-phenyl, —SH, —C≡N, —CF₃,    C₁-C₆ alkoxy, NH₂, NH(C₁-C₆ alkyl), and N—(C₁-C₆ alkyl)(C₁-C₆    alkyl);-   R₂₁₀ at each occurrence is independently selected from the group    consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; C₂-C₆ alkenyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; C₂-C₆ alkenyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; halogen; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy, —NR₂₂₀R₂₂₅;    OH; C≡N; C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; —CO—(C₁-C₄ alkyl); _SO_(2—)NR₂₃₅R₂₄₀; —CO—NR₂₃₅R₂₄₀;    —SO₂—(C₁-C₄ alkyl); and ═O;-   R₂₁₅ at each occurrence is independently selected from the group    consisting of C₁-C₆ alkyl, —(CH₂)₀₋₂-(aryl), C₂-C₆ alkenyl, C₂-C₆    alkynyl, C₃-C₇ cycloalkyl, and —(CH₂)₀₋₂-(heteroaryl),    —(CH₂)₀₋₂-(heterocycloalkyl); wherein the aryl group at each    occurrence is optionally substituted with 1, 2, or 3 groups that are    independently R₂₀₅ or R₂₁₀; wherein the heterocycloalkyl group at    each occurrence is optionally substituted with 1, 2, or 3 R₂₁₀;    wherein each heteroaryl group at each occurrence is optionally    substituted with 1, 2, or 3 R₂₁₀;    -   R₂₂₀ and R₂₂₅ at each occurrence are independently selected from        the group consisting of —H, —C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl,        amino C₁-C₆ alkyl; halo C₁-C₆ alkyl; —C₃-C₇ cycloalkyl, —(C₁-C₂        alkyl)-(C₃-C₇ cycloalkyl), —(C₁-C₆ alkyl)-O—(C₁-C₃ allyl),        —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₁-C₆ alkyl chain with one        double bond and one triple bond, -aryl, -heteroaryl, and        -heterocycloalkyl;        -   wherein the aryl group at each occurrence is optionally            substituted with 1, 2, or 3 groups that are independently            R₂₀₅ or R₂₁₀;        -   wherein the heterocycloalkyl group at each occurrence is            optionally substituted with 1, 2, or 3 R₂₁₀;        -   wherein each heteroaryl group at each occurrence is            optionally substituted with 1, 2, or 3 R₂₁₀;-   R₂₃₅ and R₂₄₀ at each occurrence are independently H, or C₁-C₆    alkyl;-   R₂₄₅ and R₂₅₀ at each occurrence are independently selected from the    group consisting of H, C₁-C₄ alkyl, C₁-C₄ alkylaryl, C₁-C₄    alkylheteroaryl, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy,    —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and    phenyl; or    R₂₄₅ and R₂₅₀ are taken together with the carbon to which they are    attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon atoms,    optionally where one carbon atom is replaced by a heteroatom    selected from the group consisting of —O—, —S—, —SO₂—, and —NR₂₂₀—;-   R₂₅₅ and R₂₆₀ at each occurrence are independently selected from the    group consisting of H; C₁-C₆ alkyl optionally substituted with 1, 2,    or 3 R₂₀₅ groups; C₂-C₆ alkenyl optionally substituted with 1, 2, or    3 R₂₀₅ groups; C₂-C₆ alkynyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl); —(CH₂)₀₋₄—C₃-C₇    cycloalkyl optionally substituted with 1, 2, or 3 R₂₀₅ groups;    —(C₁-C₄ alkyl)-aryl; —(C₁-C₄ alkyl)-heteroaryl; —(C₁-C₄    alkyl)-heterocycloalkyl; -aryl; -heteroaryl; -heterocycloalkyl;    (CH₂)₁₋₄-R₂₆₅—(CH₂)₀₋₄-aryl; —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heteroaryl;    and; —(CH₂)₁₋₄-R₂₆₅—(CH₂)₀₋₄-heterocycloalkyl; wherein    -   R₂₆₅ at each occurrence is independently —O—, —S— or —N(C₁-C₆        alkyl)-;    -   each aryl or phenyl is optionally substituted with 1, 2, or 3        groups that are independently R₂₀₅, R₂₁₀, or C₁-C₆ alkyl        substituted with 1, 2, or 3 groups that are independently R₂₀₅        or R₂₁₀;    -   each heteroaryl is optionally substituted with 1, 2, 3, or 4        R₂₀₀,    -   each heterocycloalkyl is optionally substituted with 1, 2, 3, or        4 R₂₁₀.

In a further preferred embodiment [non-CH₂-phenyl embodiment; removal ofmultiple inactive compounds], Rc is selected from the group consistingof C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from the group consisting of R₂₀₅, —OC═ONR₂₃₅R₂₄₀, —S(═O)₀₋₂R₂₃₅, —NR₂₃₅C═O NR₂₃₅R₂₄₀, —C═O NR₂₃₅R₂₄₀, and—S(═O)₂ NR₂₃₅R₂₄₀; —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl wherein the cycloalkylis optionally substituted with 1, 2, or 3 groups independently selectedfrom the group consisting of R₂₀₅, —CO₂H, and —CO₂—(C₁-C₄ alkyl);—(CR₂₄₅R₂₅₀)₂₋₄-aryl; —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl,—(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl; —(CR₂₄₅R₂₅₀)₀₋₄-aryl-heteroaryl;—(CR₂₄₅R₂₅₀)₀₋₄-aryl-heterocycloalkyl; —(CR₂₄₅R₂₅₀)₀₋₄-aryl-aryl;—(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-aryl;—(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heterocycloalkyl;—(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heteroaryl;—(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-heteroaryl;—(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-heterocycloalkyl;—(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-aryl; —[C(R₂₅₅)(R₂₆₀)]₁₋₃—CO—N—(R₂₅₅)₂;—CH(aryl)₂; —CH(heteroaryl)₂; —CH(heterocycloalkyl)₂;—CH(aryl)(heteroaryl); cyclopentyl, cyclohexyl, or cycloheptyl ringfused to aryl, heteroaryl, or heterocycloalkyl wherein one carbon of thecyclopentyl, cyclohexyl, or cycloheptyl is optionally replaced with oneor two NH, NR₂₁₅, O, or S(═O)₀₋₂, and wherein the cyclopentyl,cyclohexyl, or cycloheptyl group can be optionally substituted with 1 or2 groups that are independently R₂₀₅, ═O, —CO—NR₂₃₅R₂₄₀, or —SO₂—(C₁-C₄alkyl); C₂-C₁₀ alkenyl optionally substituted with 1, 2, or 3 R₂₀₅groups; C₂-C₁₀ alkynyl optionally substituted with 1, 2, or 3 R₂₀₅groups; —(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH)—(CH₂)₀₋₁-aryl;—(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH—(CH₂)₀₋₁-heteroaryl; —CH(-aryl or-heteroaryl)-CO—O(C₁-C₄ alkyl); —CH(—CH₂—OH)—CH(OH)-phenyl-NO₂; (C₁-C₆alkyl)-O—(C₁-C₆ alkyl)-OH; —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂; —H; and—(CH₂)₀₋₆—C(═NR₂₃₅)NR₂₃₅R₂₄₀); wherein

-   each aryl is optionally substituted with 1, 2, or 3 R₂₀₀;-   each heteroaryl is optionally substituted with 1, 2, 3, or 4 R₂₀₀;-   each heterocycloalkyl is optionally substituted with 1, 2, 3, or 4    R₂₁₀;-   R₂₀₀ at each occurrence is independently selected from the group    consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; OH; —NO₂; halogen; —CO₂H; C≡N; —(CH₂)₀₋₄—CO—NR₂₂₀R225;    —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl); —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl);    —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl); —(CH₂)₀₋₄—CO—(C₃-C₇ cycloalkyl);    —(CH₂)₀₋₄—CO-aryl; —(CH₂)₀₋₄—CO-heteroaryl;    —(CH₂)₀₋₄—CO-heterocycloalkyl; —(CH₂)₀₋₄—CO—O—R₂₁₅;    —(CH₂)₀₋₄—SO₂—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl);    —(CH₂)₀₋₄—SO_(2—)(C₁-C₁₂ alkyl); —(CH₂)₀₋₄—SO₂—(C₃-C₇ cycloalkyl);    —(CH₂)₀₋₄—N(H or R₂₁₅)—CO—O—R₂₁₅; —(CH₂)₀₋₄—N(H or    R₂₁₅)—CO—N(R₂₁₅)₂; —(CH₂)₀₋₄—N—CS—N(R₂₁₅)₂; —(CH₂)₀₋₄—N(—H or    R₂₁₅)—CO—R₂₂₀; —(CH₂)₀₋₄—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl);    —(CH₂)₀₋₄—O—P(O)—(OR₂₄₀)₂; —(CH₂)₀₋₄—O—CO—N(R₂₁₅)₂;    —(CH₂)₀₋₄—O—CS—N(R₂₁₅)₂; —(CH₂)₀₋₄—O—(R₂₁₅);    —(CH₂)₀₋₄—O—(R₂₁₅)—COOH; —(CH₂)₀₋₄—S—(R₂₁₅); —(CH₂)₀₋₄—O—(C₁-C₆    alkyl optionally substituted with 1, 2, 3, or 5 —F); C₃-C₇    cycloalkyl; C₂-C₆ alkenyl optionally substituted with 1 or 2 R₂₀₅    groups; C₂-C₆ alkynyl optionally substituted with 1 or 2 R₂₀₅    groups; —(CH₂)₀₋₄—N(H or R₂₁₅)—SO₂—R₂₂₀; and —(CH₂)₀₋₄—C₃-C₇    cycloalkyl;    -   wherein each aryl group at each occurrence is optionally        substituted with 1, 2, or 3 groups that are independently R₂₀₅,        R₂₁₀ or C₁-C₆ alkyl substituted with 1, 2, or 3 groups that are        independently R₂₀₅ or R₂₁₀;    -   wherein each heterocycloalkyl group at each occurrence is        optionally substituted with 1, 2, or 3 groups that are        independently R₂₁₀;    -   wherein each heteroaryl group at each occurrence is optionally        substituted with 1, 2, or 3 groups that are independently R₂₀₅,        R₂₁₀, or C₁-C₆ alkyl substituted with 1, 2, or 3 groups that are        independently R₂₀₅ or R₂₁₀;-   R₂₀₅ at each occurrence is independently selected from the group    consisting of C₁-C₆ alkyl, halogen, —OH, —O-phenyl, —SH, —C≡N, —CF₃,    C₁-C₆ alkoxy, NH₂, NH(C₁-C₆ alkyl), and N—(C₁-C₆ alkyl)(C₁-C₆    alkyl);-   R₂₁₀ at each occurrence is independently selected from the group    consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; C₂-C₆ alkenyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; C₂-C₆ alkynyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; halogen; C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, —NR₂₂₀R₂₂₅;    OH; C≡N; C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; —CO—(C₁-C₄ alkyl); _SO_(2—)NR₂₃₅R₂₄₀; —CO—NR₂₃₅R₂₄₀;    —SO₂—(C₁-C₄ alkyl); and ═O;-   R₂₁₅ at each occurrence is independently selected from the group    consisting of C₁-C₆ alkyl, —(CH₂)₀₋₂-(aryl), C₂-C₆ alkenyl, C₂-C₆    alkynyl, C₃-C₇ cycloalkyl, and —(CH₂)₀₋₂-(heteroaryl),    —(CH₂)₀₋₂-(heterocycloalkyl); wherein the aryl group at each    occurrence is optionally substituted with 1, 2, or 3 groups that are    independently R₂₀₅ or R₂₁₀; wherein the heterocycloalkyl group at    each occurrence is optionally substituted with 1, 2, or 3 R₂₁₀;    wherein each heteroaryl group at each occurrence is optionally    substituted with 1, 2, or 3 R₂₁₀;    -   R₂₂₀ and R₂₂₅ at each occurrence are independently selected from        the group consisting of —H, —C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl,        amino C₁-C₆ alkyl; halo C₁-C₆ alkyl; —C₃-C₇ cycloalkyl, —(C₁-C₂        alkyl)-(C₃-C₇ cycloalkyl), —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl),        —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₁-C₆ alkyl chain with one        double bond and one triple bond, -aryl, -heteroaryl, and        -heterocycloalkyl;        -   wherein the aryl group at each occurrence is optionally            substituted with 1, 2, or 3 groups that are independently            R₂₀₅ or R₂₁₀;        -   wherein the heterocycloalkyl group at each occurrence is            optionally substituted with 1, 2, or 3 R₂₁₀;        -   wherein each heteroaryl group at each occurrence is            optionally substituted with 1, 2, or 3 R₂₁₀;-   R₂₃₅ and R₂₄₀ at each occurrence are independently H, or C₁-C₆    alkyl;-   R₂₄₅ and R₂₅₀ at each occurrence are independently selected from the    group consisting of H, C₁-C₄ alkyl, C₁-C₄ alkylaryl, C₁-C₄    alkylheteroaryl, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy,    —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and    phenyl; or    R₂₄₅ and R₂₅₀ are taken together with the carbon to which they are    attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon atoms,    optionally where one carbon atom is replaced by a heteroatom    selected from the group consisting of —O—, —S—, —SO₂—, and —NR₂₂₀—;-   R₂₅₅ and R₂₆₀ at each occurrence are independently selected from the    group consisting of H; C₁-C₆ alkyl optionally substituted with 1, 2,    or 3 R₂₀₅ groups; C₂-C₆ alkenyl optionally substituted with 1, 2, or    3 R₂₀₅ groups; C₂-C₆ alkynyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl); —(CH₂)₀₋₄—C₃-C₇    cycloalkyl optionally substituted with 1, 2, or 3 R₂₀₅ groups;    —(C₁-C₄ alkyl)-aryl; —(C₁-C₄ alkyl)-heteroaryl; —(C₁-C₄    alkyl)-heterocycloalkyl; -aryl; -heteroaryl; -heterocycloalkyl;    (CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-aryl; —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heteroaryl;    and; —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heterocycloalkyl; wherein    -   R₂₆₅ at each occurrence is independently —O—, —S— or —N(C₁-C₆        alkyl)-;    -   each aryl or phenyl is optionally substituted with 1, 2, or 3        groups that are independently R₂₀₅, R₂₁₀, or C₁-C₆ alkyl        substituted with 1, 2, or 3 groups that are independently R₂₀₅        or R₂₁₀;    -   each heteroaryl is optionally substituted with 1, 2, 3, or 4        R₂₀₀,    -   each heterocycloalkyl is optionally substituted with 1, 2, 3, or        4 R₂₁₀.

In a preferred embodiment, the invention encompasses a compound offormula (I), or a pharmaceutically acceptable salt or ester thereof,wherein B is H or C₁-C₁₀ straight or branched chain alkyl; R₂₀, R₂ andR₃ are H; n is 0; R₁ is 3,5-difluorophenyl; and Rc is

where R in this preferred embodiment is C₁-C₄ straight or branched chainalkyl, optionally substituted with —OB or —SO₂B.

The invention encompasses a method of treating a patient who has, or inpreventing a patient from getting, a disease or condition selected fromthe group consisting of Alzheimer's disease, for helping prevent ordelay the onset of Alzheimer's disease, for treating patients with mildcognitive impairment (MCI) and preventing or delaying the onset ofAlzheimer's disease in those who would progress from MCI to AD, fortreating Down's syndrome, for treating humans who have HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treatingcerebral amyloid angiopathy and preventing its potential consequences,i.e. single and recurrent lobar hemorrhages, for treating otherdegenerative dementias, including dementias of mixed vascular anddegenerative origin, dementia associated with Parkinson's disease,dementia associated with progressive supranuclear palsy, dementiaassociated with cortical basal degeneration, diffuse Lewy body type ofAlzheimer's disease and who is in need of such treatment which comprisesadministration of a therapeutically effective amount of a compoundselected from the group consisting of a substituted aminoalcohol of theformula (I):

or pharmaceutically acceptable salt or ester thereof,

-   wherein B is H, C₁-C₁₀ straight or branched chain alkyl;-   wherein R₂₀ is H or C₁₋₆ alkyl or alkenyl-   wherein n is 0 or 1;-   wherein R₁ is:    -   (I) C₁-C₆ alkyl, optionally substituted with one, two or three        substit uents selected from the group consisting of C₁-C₃ alkyl,        C₁-C₇ alkyl (optionally substituted with C₁-C₃ alkyl and C₁-C₃        alkoxy), —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆        alkyl, —OC═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as        defined above,    -   (II) —CH₂—S(O)₀₋₂—(C₁-C₆ alkyl),    -   (III) —CH₂—CH₂—S(O)₀₋₂—(C₁-C₆ alkyl),    -   (IV) C₂-C₆ alkenyl with one or two double bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl,    -   (V) C₂-C₆ alkynyl with one or two triple bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl,    -   (VI) —(CH₂)_(n1)—(R_(1-aryl)) where n₁ is zero or one and where        R_(1-aryl) is phenyl, 1-naphthyl, 2-naphthyl and indanyl,        indenyl, dihydronaphthalyl, tetralinyl optionally substituted        with one, two, three or four of the following substituents on        the aryl ring:        -   (A) C₁-C₆ alkyl optionally substituted with one, two or            three substituents selected from the group consisting of            C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b)            where R_(1-a) and R_(1-b) are as defined above, —C≡N, —CF₃,            C₁-C₃ alkoxy,        -   (B) C₂-C₆ alkenyl with one or two double bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁-C₆ alkyl,        -   (C) C₂-C₆ alkynyl with one or two triple bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁-C₆ alkyl,        -   (D) —F, Cl, —Br and —I,        -   (F) —C₁-C₆ alkoxy optionally substituted with one, two or            three —F,        -   (G) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as            defined below,        -   (H) —OH,        -   (I) —C≡N,        -   (J) C₃-C₇ cycloalkyl, optionally substituted with one, two            or three substituents selected from the group consisting of            —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,            —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆            alkyl,        -   (K) —CO—(C₁-C₄ alkyl),        -   (L) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above,        -   (M) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above, or        -   (N) —SO₂—(C₁-C₄ alkyl),    -   (VII) —(CH₂)_(n1)—(R_(1-heteroaryl)) where n₁ is as defined        above and where R_(1-heteroaryl) is selected from the group        consisting of:        -   (A) pyridinyl,        -   (B) pyrimidinyl,        -   (C) quinolinyl,        -   (F) benzothienyl,        -   (G) indolyl,        -   (H) indolinyl,        -   (I) pryidazinyl,        -   (J) pyrazinyl,        -   (K) isoindolyl,        -   (L) isoquinolyl,        -   (M) quinazolinyl,        -   (N) quinoxalinyl,        -   (O) phthalazinyl,        -   (P) imidazolyl,        -   (Q) isoxazolyl,        -   (R) pyrazolyl,        -   (S) oxazolyl,        -   (T) thiazolyl,        -   (U) indolizinyl,        -   (V) indazolyl,        -   (W) benzothiazolyl,        -   (X) benzimidazolyl,        -   (Y) benzofuranyl,        -   (Z) furanyl,        -   (AA) thienyl,        -   (BB) pyrrolyl,        -   (CC) oxadiazolyl,        -   (DD) thiadiazolyl,        -   (EE) triazolyl,        -   (FF) tetrazolyl,        -   (II) oxazolopyridinyl,        -   (JJ) imidazopyridinyl,        -   (KK) isothiazolyl,        -   (LL) naphthyridinyl,        -   (MM) cinnolinyl,        -   (NN) carbazolyl,        -   (OO) beta-carbolinyl,        -   (PP) isochromanyl,        -   (QQ) chromanyl,        -   (SS) tetrahydroisoquinolinyl,        -   (TT) isoindolinyl,        -   (UU) isobenzotetrahydrofuranyl,        -   (VV) isobenzotetrahydrothienyl,        -   (WW) isobenzothienyl,        -   (XX) benzoxazolyl,        -   (YY) pyridopyridinyl,        -   (ZZ) benzotetrahydrofuranyl,        -   (AAA) benzotetrahydrothienyl,        -   (BBB) purinyl,        -   (CCC) benzodioxolyl,        -   (DDD) triazinyl,        -   (EEE) phenoxazinyl,        -   (FFF) phenothiazinyl,        -   (GGG) pteridinyl,        -   (HHH) benzothiazolyl,        -   (III) imidazopyridinyl,        -   (JJJ) imidazothiazolyl,        -   (KKK) dihydrobenzisoxazinyl,        -   (LLL) benzisoxazinyl,        -   (MMM) benzoxazinyl,        -   (NNN) dihydrobenzisothiazinyl,        -   (OOO)benzopyranyl,        -   (PPP) benzothiopyranyl,        -   (QQQ) coumarinyl,        -   (RRR) isocoumarinyl,        -   (SSS) chromonyl,        -   (TTT) chromanonyl, and        -   (UUU) pyridinyl-N-oxide,        -    where the R_(1-heteroaryl) group is bonded to —CH₂)_(n1)—            by any ring atom of the parent R_(N-heteroaryl) group            substituted by hydrogen such that the new bond to the            R_(1-heteroaryl) group replaces the hydrogen atom and its            bond, where heteroaryl is optionally substituted with one,            two, three or four of:        -   (1) C₁-C₆ alkyl optionally substituted with one, two or            three substituents selected from the group consisting of            C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b)            where R_(1-a) and R_(1-b) are as defined above, —C≡N, —CF₃,            C₁-C₃ alkoxy,        -   (2) C₂-C₆ alkenyl with one or two double bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁-C₆ alkyl,        -   (3) C₂-C₆ alkynyl with one or two triple bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁-C₆ alkyl,        -   (4) —F, Cl, —Br and —I,        -   (6) —C₁-C₆ alkoxy optionally substituted with one, two, or            three —F,        -   (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as            defined below,        -   (8) —OH,        -   (9) —C≡N,        -   (10) C₃-C₇ cycloalkyl, optionally substituted with one, two            or three substituents selected from the group consisting of            —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,            —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆            alkyl,        -   (11) —CO—(C₁-C₄ alkyl),        -   (12) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above,        -   (13) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above, or        -   (14) —SO₂—(C₁-C₄ alkyl), with the proviso that when n, is            zero R_(1-heteroaryl) is not bonded to the carbon chain by            nitrogen,    -   (VIII) —(CH₂)_(n1)—(R_(1-heterocycle)) where n₁ is as defined        above and R_(1-heterocycle) is selected from the group        consisting of:        -   (A) morpholinyl,        -   (B) thiomorpholinyl,        -   (C) thiomorpholinyl S-oxide,        -   (D) thiomorpholinyl S,S-dioxide,        -   (E) piperazinyl,        -   (F) homopiperazinyl,        -   (G) pyrrolidinyl,        -   (H) pyrrolinyl,        -   (I) tetrahydropyranyl,        -   (J) piperidinyl,        -   (K) tetrahydrofuranyl,        -   (L) tetrahydrothienyl,        -   (M) homopiperidinyl,        -   (N) homomorpholinyl,        -   (O) homothiomorpholinyl,        -   (P) homomorpholinyl S-oxide,        -   (Q) homothiomorpholinyl S,S-dioxide, and        -   (R) oxazolidinonyl,        -    where the R_(1-heterocycle) group is bonded by any atom of            the parent R_(1-heterocycle) group substituted by hydrogen            such that the new bond to the R_(1-heterocycle) group            replaces the hydrogen atom and its bond, where heterocycle            is optionally substituted with one, two, three or four of:            -   (1) C₁-C₆ alkyl optionally substituted with one, two or                three substituents selected from the group consisting of                C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,                —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as                defined above, —C≡N, —CF₃, C₁-C₃ alkoxy,            -   (2) C₂-C₆ alkenyl with one or two double bonds,                optionally substituted with one, two or three                substituents selected from the group consisting of —F,                —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,                —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or                C₁-C₆ alkyl,            -   (3) C₂-C₆ alkynyl with one or two triple bonds,                optionally substituted with one, two or three                substituents selected from the group consisting of —F,                —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,                —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or                C₁-C₆ alkyl,            -   (4) —F, Cl, —Br and —I,            -   (5) C₁-C₆ alkoxy,            -   (6) —C₁-C₆ alkoxy optionally substituted with one, two,                or three —F,            -   (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as                defined below,            -   (8) —OH,            -   (9) —C≡N,            -   (10) C₃-C₇ cycloalkyl, optionally substituted with one,                two or three substituents selected from the group                consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃                alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are                —H or C₁-C₆ alkyl,            -   (11) —CO—(C₁-C₄ alkyl),            -   (12) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are                as defined above,            -   (13) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are                as defined above,            -   (14) —O₂—(C₁-C₄ alkyl), or            -   (15) ═O, with the proviso that when n₁ is zero                R_(1-heterocycle) is not bonded to the carbon chain by                nitrogen; or    -   (IX) G-L-A-W-    -   where A is:        -   (I) phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl,            dihydronaphthalyl, tetralinyl, cyclopentyl, cyclohexyl, and            cycloheptyl optionally substituted with one or two of the            following substituents on the ring:        -   (A) —NO₂,        -   (B) —C≡N,        -   (C) —N(R)CO(R′) R, R′ defined below        -   (D) —CO—O—R_(N-5) where R_(N-5) is selected from the group            consisting of:            -   (a) C₁-C₆ alkyl, and            -   (b) —(CH₂)₀₋₂-(R_(1-aryl)) where R_(1-aryl) is as                defined above,        -   (E) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,        -   (F) —O—(C₂-C₆ alkyl)-COOH,        -   (G) —NRR′ where R, R′ are H, C₁-C₆ alkyl,            —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as defined above,        -   (H) —SR where R is H, C₁-C₆ alkyl, —(CH₂)₀₋₂—(R_(1-aryl))            where R_(1-aryl) is as defined above,        -   (I) —CH₂OH,        -   (J) —CO—(C₁-C₆) alkyl,        -   (K) —CONRR′ where R, R′ are H, C₁-C₆ alkyl,            —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as defined above,        -   (L) —SO₂NRR′ where R, R′ are H, C₁-C₆ alkyl,        -   (M) —COOH,        -   (N) —C₁-C₆ alkyl,        -   (O) —C₂-C₆ alkenyl with one or two double bonds, or        -   (P) —C₂-C₆ alkynyl with one or two triple bonds,        -   wherein each of (N), (O) and (P) may be optionally            substituted by one to three of —CF₃, —F, —Cl, —Br, —I, C₁-C₃            alkyoxy, —OCF₃, —NH₂, —OH, and —CN, and provided that G, L            and W may not all be absent;        -   (II) R_(1-heteroaryl) as defined above, where the            R_(1-heteroaryl) group bonds to the subsistent W by a ring            carbon atom, and where R_(1-heteroaryl) is optionally            substituted with one, two, three, or four substituents            independently chosen from the group consisting of:        -   (A) —NO₂,        -   (B) —C≡N,        -   (C) —N(R)CO(R′) where R, R′ are defined below,        -   (D) —CO—O—R_(N-5) where R_(N-5) is selected from the group            consisting of:            -   (a) C₁-C₆ alkyl, and            -   (b) —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as                defined above,        -   (E) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,        -   (F) —O—(C₂-C₆ alkyl)-COOH,        -   (G) —NRR′ where R, R′ are independently H, C₁-C₆ alkyl, and            —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as defined above,        -   (H) —SR where R and R_(1-aryl) are as defined above,        -   (I) —CH₂OH,        -   (J) —CO—(C₁-C₆) alkyl,        -   (K) —CONRR′ where R, R′ and R_(-aryl) are as defined above,        -   (L) —SO₂NRR′ where R, R′ are H, C₁-C₆ alkyl,        -   (M) —COOH,        -   (N) —C₁-C₆ alkyl,        -   (O) —C₂-C₆ alkenyl with one or two double bonds, and        -   (P) —C₂-C₆ alkynyl with one or two triple bonds,        -   wherein each of (N), (O) and (P) may be optionally            substituted by one to three substituent indepedendly chosen            from the group consisting of —CF₃, —F, —Cl, —Br, —I, C₁-C₃            alkyoxy, —OCF₃, —NH₂, —OH, and —CN, and provided that G, L            and W may not all be absent, or        -   (III) R_(1-heterocycle) as defined above:    -   where the R_(1-heterocycle) group bonds to the subsistent W by a        ring carbon atom, and where R_(1-heteroaryl) is optionally        substituted with one to two substituents independently chosen        from the group consisting of        -   (1) ═O,        -   (2) C₁-C₃ alkyl,        -   (3) —CF₃,        -   (4) —F, Cl, —Br or —I,        -   (5) C₁-C₃ alkoxy,        -   (6) —O—CF₃,        -   (7) —NH₂,        -   (8) —OH, and        -   (9) —C≡N,

and provided that G, L and W may not all be absent,

where W is —S(O)₀₋₂—, —O—, —N—, or absent, and N is optionallysubstituted with C₁-C₄ alkyl;

where L is —CO—, —S(O)₁₋₂—, —O—, —C(Ra)(Rb)O—, —OC(Ra)(Rb)—, —N(Ra)—,—CON(Ra)—, —N(Ra)CO—, —C(Ra)(Rb)—, —C(OH)Ra—, —SO₂NRa—, —N(Ra)SO₂—,—N(Ra)CON(Rb)—, N(Ra)CSN(Rb)—, —OCOO—, —NCOO—, OCON(Ra)—, a bond, or Lis absent when G is absent, and where Ra and Rb are independently H,C₁-C₄ alkyl which are optionally substituted. with OH, C₁-C₄ alkoxy, andup to five —F;

-   -   where G is:    -   (I) —C₁-C₁₀ alkyl optionally substituted with one substituent        selected from the group consisting of:        -   (A) —COOH,        -   (B) —CO—O—(C₁-C₄ alkyl),        -   (C) C₁-C₆ alkoxy,        -   (D) —OH,        -   (E) —NH₂,        -   (F) —C₁-C₆ alkyl optionally substituted with one to five —F        -   (G) —(C₁-C₁₀ alkyl)-O—(C₁-C₃ alkyl),        -   (H) —C₂-C₁₀ alkenyl with one or two double bonds,        -   (I) —C₂-C₁₀ alkynyl with one or two triple bonds,        -   (J) —C₄-C₁₀ hydrocarbyl chain with one double bond and one            triple bond,        -   (K) —R_(1-aryl) where R_(1-aryl), is as defined above,        -   (L) —R_(1-heteroaryl) where R_(1-heteroaryl) is as defined            above,    -   (II) —(CH₂)₀₋₃—(C₃-C₇) cycloalkyl where cycloalkyl can be        optionally substituted with one, two or three substituents        selected from the group consisting of:        -   (A) —COOH,        -   (B) —CO—O—(C₁-C₄ alkyl),        -   (C) C₁-C₆ alkoxy,        -   (D) —OH,        -   (E) —NH₂,        -   (F) —C₁-C₆ alkyl optionally substituted with one to five —F        -   (G) —(C₁-C₁₀ alkyl)-O—(C₁-C₃ alkyl),        -   (H) —C₂-C₁₀ alkenyl with one or two double bonds,        -   (I) —C₂-C₁₀ alkynyl with one or two triple bonds,        -   (J) —C₄-C₁₀ hydrocarbyl chain with one double bond and one            triple bond,        -   (K) —R_(1-aryl) where R_(1-aryl) is as defined above,        -   (L) —R_(1-heteroaryl) where R_(1-heteroaryl) is as defined            above,    -   (III) —(CR′R″)₀₋₄—R_(1-aryl) where R′, R″ and R_(1-aryl) are as        defined above,    -   (IV) —(CH₂)₀₋₄—R_(1-heteroaryl) where R_(1-heteroaryl) is as        defined above,    -   (V) —(CH₂)₀₋₄—R_(1-heterocycle) where R_(1-heterocycle) is as        defined above,    -   (VI) —C(R_(C-1))(R_(C-2))—CO—NH—R_(C-3) where R_(C-1) and        R_(C-2) are independently selected from the group consisting of:        -   (A) —H,        -   (B) —C₁-C₆ alkyl,        -   (C) —(C₀-C₄ alkyl)-R_(1-aryl), wherein R_(1-aryl) is as            defined above,        -   (D) —(C₀-C₄ alkyl)-R_(1-heteroaryl), wherein            R_(1-heteroaryl) is as defined above,        -   (E) —(C₀-C₄ alkyl)-R_(1-heterocycle), wherein            R_(1-heterocycle) is as defined above,        -   (F) —(CH₂)₁₋₄—OH        -   (G) —CH₂)₁₋₄—R_(C-4)—(CH₂)₁₋₄—R_(C′-aryl) where R_(C-4) is            —O—, —S— or        -   (H) —NR_(C-5)— where R_(C-5) is — or C₁-C₆ alkyl, and where            R_(C′-aryl) is defined above, and        -   (I) —(CH₂)₁₋₄—R_(C-4)—(CH₂)₁₋₄—R_(C-heteroaryl) where            R_(C-4) and R_(C-heteroaryl) are as defined above,        -   wherein in (C), (D) and (E) C₀ is merely a bond, and where            R_(C-3) is:            -   (a) —H,            -   (b) —C₁-C₆ alkyl,            -   (c) —(C₀-C₄ alkyl)-R_(1-aryl) where R_(1-aryl) is as                defined above,            -   (d) —(C₀-C₄ alkyl)-R_(1-heteroaryl) where                R_(1-heteroaryl) is as defined above,            -   (e) —(C₀-C₄ alkyl)-R_(1-heterocycle) where                R_(1-heterocycle) is as defined above,    -   (VII) -cyclopentyl or -cyclohexyl ring fused to a phenyl or        heteroaryl ring where heteroaryl is as defined above and phenyl        and heteroaryl are optionally substituted with one, two or three        of:        -   (C) C₁-C₆ alkyl,        -   (B) —CF₃,        -   (C) —F, Cl, —Br and —I,        -   (D) C₁-C₃ alkoxy,        -   (E) —OCF₃,        -   (F) —NH₂,        -   (G) —OH,        -   (H) —C≡N,        -   (I) —NO₂        -   (J) —CO—OH,        -   (K) —CO—O—R_(N-5) where R_(N-5) is selected from the group            consisting of:            -   (a) C₁-C₆ alkyl, and            -   (b) —(C₀-C₂ alkyl)-(R_(1-aryl)) where R_(1-aryl) is as                defined above,        -   (L) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,        -   (M) —O—(C₂-C₅ alkyl)-COOH, or        -   (N) —OR where R is as defined above,        -   (O) —NR—R′ where R and R′ are as defined above,        -   (P) —SR where R is as defined above,        -   (Q) —CF₃,        -   (R) —OCF₃,        -   (S) —N(R)COR′ where R, R′ are as defined above,        -   (T) —NRR′ where R, R′ are as defined above,        -   (U) —SR where R is as defined above,        -   (V) —CH₂OH,        -   (W) —CO—(C₁-C₆) alkyl,        -   (X) —CONRR′ where R, R′ are as defined above, or        -   (Y) —SO₂NRR′ where R is as defined above, or    -   (VIII) —(CH₂)₂—O—(CH₂)₂—OH; wherein R₂ is selected from the        group consisting of:    -   (I) —H,    -   (II) C₁-C₆ alkyl, optionally substituted with one, two or three        substituents selected from the group consisting of C₁-C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (III) —(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is R_(1-aryl) or        R_(1-heteroaryl) where R_(1-aryl) and R_(1-heteroaryl) are as        defined above;        -   (IV) C₂-C₆ alkenyl with one or two double bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁-C₆ alkyl,    -   (V) C₂-C₆ alkynyl with one or two triple bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl, and    -   (VI) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with        one, two or three substituents selected from the group        consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆        alkyl; wherein R₃ is selected from the group consisting of:    -   (I) —H,    -   (II) C₁-C₆ alkyl, optionally substituted with one, two or three        substituents selected from the group consisting of C₁-C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (III) —(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is R_(1-aryl) or        R_(1-heteroaryl) where R_(1-aryl) and R_(1-heteroaryl) are as        defined above;    -   (IV) C₂-C₆ alkenyl with one or two double bonds,    -   (V) C₂-C₆ alkynyl with one or two triple bonds, and    -   (VI) —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, optionally substituted with        one, two or three substituents selected from the group        consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆        alkyl,        and where R₂ and R₃ are taken together with the carbon to which        they are attached to form a carbocycle of three, four, five, six        and seven carbon atoms, optionally where one carbon atom is        replaced by a heteroatom selected from the group consisting of        —O—, —S—, —SO₂—, —NR_(N-2)—, where R_(N-2) is as defined below;        and

-   wherein R_(C) is selected from the group consisting of C₁-C₁₀ alkyl    optionally substituted with 1, 2, or 3 groups independently selected    from the group consisting of R₂₀₅, —OC═O NR₂₃₅R₂₄₀, —S(═O)₀₋₂ R₂₃₅,    —NR₂₃₅C═O NR₂₃₅R₂₄₀, —C═O NR₂₃₅R₂₄₀, and —S(═O)₂ NR₂₃₅R₂₄₀;    —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl wherein the cycloalkyl is optionally    substituted with 1, 2, or 3 groups independently selected from the    group consisting of R₂₀₅, —CO₂H, and —CO₂—(C₁-C₄ alkyl);    —(CR₂₄₅R₂₅₀)₀₋₄-aryl; —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl,    —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl; —(CR₂₄₅R₂₅₀)₀₋₄-aryl-heteroaryl;    —(CR₂₄₅R₂₅₀)₀₋₄-aryl-heterocycloalkyl; —(CR₂₄₅R₂₅₀)₀₋₄-aryl-aryl;    —(CR₂₄₅R₂₀₀)₀₋₄-heteroaryl-aryl;    —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heterocycloalkyl;    —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heteroaryl;    —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-heteroaryl;    —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-heterocycloalkyl;    —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-aryl;    —[C(R₂₅₅)(R₂₆₀)]₁₋₃—CO—N—(R₂₅₅)₂; —CH(aryl)₂; —CH(heteroaryl)₂;    —CH(heterocycloalkyl)₂; —CH(aryl)(heteroaryl); cyclopentyl,    cyclohexyl, or cycloheptyl ring fused to aryl, heteroaryl, or    heterocycloalkyl wherein one carbon of the cyclopentyl, cyclohexyl,    or cycloheptyl is optionally replaced with one or two NH, NR₂₁₅, O,    or S(═O)₀₋₂, and wherein the cyclopentyl, cyclohexyl, or cycloheptyl    group can be optionally substituted with 1 or 2 groups that are    independently R₂₀₅, ═O, —CO—NR₂₃₅R₂₄₀, or —SO₂—(C₁-C₄ alkyl); C₂-C₁₀    alkenyl optionally substituted with 1, 2, or 3 R₂₀₅ groups; C₂-C₁₀    alkynyl optionally substituted with 1, 2, or 3 R₂₀₅ groups;    —(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH)—(CH₂)₀₋₁-aryl;    —(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH—(CH₂)₀₋₁-heteroaryl; —CH(-aryl or    -heteroaryl)-CO—O(C₁-C₄ alkyl); —CH(—CH₂—OH)—CH(OH)-phenyl-NO₂;    (C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-OH; —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂; —H;    and —(CH₂)₀₋₆—C(═NR₂₃₅)(NR₂₃₅R₂₄₀); wherein    -   each aryl is optionally substituted with 1, 2, or 3 R₂₀₀;    -   each heteroaryl is optionally substituted with 1, 2, 3, or 4        R₂₀₀;    -   each heterocycloalkyl is optionally substituted with 1, 2, 3, or        4 R₂₁₀;    -   R₂₀₀ at each occurrence is independently selected from the group        consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3        R₂₀₅ groups; OH; —NO₂; halogen; —CO₂H; C≡N;        —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl);        —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl); —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl);        —(CH₂)₀₋₄—CO—(C₃-C₇ cycloalkyl); —(CH₂)₀₋₄—CO-aryl;        —(CH₂)₀₋₄—CO-heteroaryl; —(CH₂)₀₋₄—CO-heterocycloalkyl;        —(CH₂)₀₋₄—CO—O—R₂₁₅; —(CH₂)₀₋₄—SO₂—NR₂₂₀R₂₂₅;        —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl); —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl);        —(CH₂)₀₋₄—SO₂—(C₃-C₇ cycloalkyl); —(CH₂)₀₋₄—N(H or        R₂₁₅)—CO—O—R₂₁₅; —(CH₂)₀₋₄—N(H or R₂₁₅)—CO—N(R₂₁₅)₂;        —(CH₂)₀₋₄—N—CS—N(R₂₁₅)₂; —(CH₂)₀₋₄—N(—H or R₂₁₅)—CO—R₂₂₀;        —(CH₂)₀₋₄—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl);        —(CH₂)₀₋₄—O—P(O)—(OR₂₄₀)₂; —(CH₂)₀₋₄—O—CO—N(R₂₁₅)₂;        —(CH₂)₀₋₄—O—CS—N(R₂₁₅)₂; —(CH₂)₀₋₄—O—(R₂₁₅);        —(CH₂)₀₋₄—O—(R₂₁₅)—COOH; —(CH₂)₀₋₄—S—(R₂₁₅); —(CH₂)₀₋₄—O—(C₁-C₆        alkyl optionally substituted with 1, 2, 3, or 5-F); C₃-C₇        cycloalkyl; C₂-C₆ alkenyl optionally substituted with 1 or 2        R₂₀₅ groups; C₂-C₆ alkynyl optionally substituted with 1 or 2        R₂₀₅ groups; —(CH₂)₀₋₄—N(H or R₂₁₅)—SO₂—R₂₂₀; and        —(CH₂)₀₋₄—C₃-C₇ cycloalkyl;        -   wherein each aryl group at each occurrence is optionally            substituted with 1, 2, or 3 groups that are independently            R₂₀₅, R₂₁₀ or C₁-C₆ alkyl substituted with 1, 2, or 3 groups            that are independently R₂₀₅ or R₂₁₀;        -   wherein each heterocycloalkyl group at each occurrence is            optionally substituted with 1, 2, or 3 groups that are            independently R₂₁₀;        -   wherein each heteroaryl group at each occurrence is            optionally substituted with 1, 2, or 3 groups that are            independently R₂₀₅, R₂₁₀, or C₁-C₆ alkyl substituted with 1,            2, or 3 groups that are independently R₂₀₅ or R₂₁₀;    -   R₂₀₅ at each occurrence is independently selected from the group        consisting of C₁-C₆ alkyl, halogen, —OH, —O-phenyl, —SH, —C≡N,        —CF₃, C₁-C₆ alkoxy, NH₂, NH(C₁-C₆ alkyl), and N—(C₁-C₆        alkyl)(C₁-C₆ alkyl);    -   R₂₁₀ at each occurrence is independently selected from the group        consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3        R₂₀₅ groups; C₂-C₆ alkenyl optionally substituted with 1, 2, or        3 R₂₀₅ groups; C₂-C₆ alkynyl optionally substituted with 1, 2,        or 3 R₂₀₅ groups; halogen; C₁-C₆ alkoxy, C₁-C₆ haloalkoxy;        —NR₂₂₀R₂₂₅; OH; C≡N; C₃-C₇ cycloalkyl optionally substituted        with 1, 2, or 3 R₂₀₅ groups; —CO—(C₁-C₄ alkyl); SO₂NR₂₃₅R₂₄₀;        —CO—NR₂₃₅R₂₄₀; —SO₂—(C₁-C₄ alkyl); and ═O;    -   R₂₁₅ at each occurrence is independently selected from the group        consisting of C₁-C₆ alkyl, —(CH₂)₀₋₂-(aryl), C₂-C₆ alkenyl,        C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, and —(CH₂)₀₋₂-(heteroaryl),        —(CH₂)₀₋₂-(heterocycloalkyl); wherein the aryl group at each        occurrence is optionally substituted with 1, 2, or 3 groups that        are independently R₂₀₅ or R₂₁₀; wherein the heterocycloalkyl        group at each occurrence is optionally substituted with 1, 2, or        3 R₂₁₀; wherein each heteroaryl group at each occurrence is        optionally substituted with 1, 2, or 3 R₂₁₀;        -   R₂₂₀ and R₂₂₅ at each occurrence are independently selected            from the group consisting of —H, —C₁-C₆ alkyl, hydroxy C₁-C₆            alkyl, amino C₁-C₆ alkyl; halo C₁-C₆ alkyl; —C₃-C₇            cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), —(C₁-C₆            alkyl)-O—(C₁-C₃ alkyl), —C₂-C₆ alkenyl, —C₂-C₆ alkynyl,            —C₁-C₆ alkyl chain with one double bond and one triple bond,            -aryl, -heteroaryl, and -heterocycloalkyl;            -   wherein the aryl group at each occurrence is optionally                substituted with 1, 2, or 3 groups that are                independently R₂₀₅ or R₂₁₀;            -   wherein the heterocycloalkyl group at each occurrence is                optionally substituted with 1, 2, or 3 R₂₁₀;            -   wherein each heteroaryl group at each occurrence is                optionally substituted with 1, 2, or 3 R₂₁₀;    -   R₂₃₅ and R₂₄₀ at each occurrence are independently H, or C₁-C₆        alkyl;    -   R₂₄₅ and R₂₅₀ at each occurrence are independently selected from        the group consisting of H, C₁-C₄ alkyl, C₁-C₄ alkylaryl, C₁-C₄        alkylheteroaryl C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄        haloalkoxy, —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, and phenyl; or    -   R₂₄₅ and R₂₅₀ are taken together with the carbon to which they        are attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon        atoms, optionally where one carbon atom is replaced by a        heteroatom selected from the group consisting of —O—, —S—,        —SO₂—, and —NR₂₂₀—;    -   R₂₅₅ and R₂₆₀ at each occurrence are independently selected from        the group consisting of H; C₁-C₆ alkyl optionally substituted        with 1, 2, or 3 R₂₀₅ groups; C₂-C₆ alkenyl optionally        substituted with 1, 2, or 3 R₂₀₅ groups; C₂-C₆ alkynyl        optionally substituted with 1, 2, or 3 R₂₀₅ groups;        —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl); —(CH₂)₀₋₄—C₃-C₇ cycloalkyl        optionally substituted with 1, 2, or 3 R₂₀₅ groups; —(C₁-C₄        alkyl)-aryl; —(C₁-C₄ alkyl)-heteroaryl; —(C₁-C₄        alkyl)-heterocycloalkyl; -aryl; -heteroaryl; -heterocycloalkyl;        —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-aryl;        —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heteroaryl; and;        —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heterocycloalkyl; wherein        -   R₂₆₅ at each occurrence is independently —O—, —S— or            —N(C₁-C₆ alkyl)-;        -   each aryl or phenyl is optionally substituted with 1, 2, or            3 groups that are independently R₂₀₅, R₂₁₀, or C₁-C₆ alkyl            substituted with 1, 2, or 3 groups that are independently            R₂₀₅ or R₂₁₀;        -   each heteroaryl is optionally substituted with 1, 2, 3, or 4            R₂₀₀,        -   each heterocycloalkyl is optionally substituted with 1, 2,            3, or 4 R₂₁₀.

In an alternative method embodiment R₁ is G-L-A-E-W-, wherein

E is a bond or C₁-C₃ alkylene;

A is:

-   -   (I) aryl or cycloalkyl where each aryl or cycloalkyl is        optionally substituted with one, two or three independently        selected R₁₀₀ groups, where R₁₀₀ is        -   (A) —NO₂,        -   (B) —C≡N,        -   (C) —N(R)CO(R′)R, where R and R′ are independently hydrogen,            C₁-C₆ alkyl, or —(CH₂)₀₋₂-aryl or —(CH₂)₀₋₂-cycloalkyl,            where each aryl or cycloalkyl is optionally substituted with            halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkyl, amino,            mono(C₁-C₆)alkylamino, or di(C₁-C₆)alkylamino,        -   (D) —CO₂—R₂₅, where R₂₅ is selected from the group            consisting of:            -   (a) C₁-C₆ alkyl,            -   (b) —(CH₂)₀₋₂-cycloalkyl,            -   (c) —(CH₂)₀₋₂-aryl, where the aryl is optionally                substituted with halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆                alkyl, amino, mono(C₁-C₆)alkylamino, or                di(C₁-C₆)alkylamino, and            -   (d) hydrogen,        -   (E) —NH—CO₂—R₂₅,        -   (F) —O—(C₂-C₆ alkyl)-CO₂H,        -   (G) —NRR′,        -   (H) —SR,        -   (I) —CH₂OH,        -   (J) —C(O)—(C₁-C₆)alkyl,        -   (K) —C(O)NRR′,        -   (L) —SO₂NRR′        -   (M) —CO₂H,        -   (N) C₁-C₆ alkyl, C₁-C₆ alkenyl with one or two double bonds,            —C₁-C₆ alkynyl with one or two triple bonds, —CF₃, —F, —Cl,            —Br, —I, C₁-C₃ alkoxy, —OCF₃, —NH₂, —OH, or —CN,        -   (O) halogen, and        -   (P) —(CH₂)₀₋₂—O—(CH₂)₀₋₂—OH;    -   (II) heteroaryl, provided that, when E is a bond, the heteroaryl        group is bonded through one of its carbon atoms to W, and where        the heteroaryl is optionally substituted with one or two        independently selected R₁₀₀ groups;    -   (III) heterocycle, provided that, when E is a bond, the        heterocycle group is bonded through one of its carbon atoms to        W, where the heterocycle is optionally substituted with one or        two independently selected R₂₀₀ groups, where R₂₀₀ is        -   (1) ═O,        -   (2) C₁-C₃ alkyl,        -   (3) —CF₃,        -   (4) —F, Cl, —Br and —I,        -   (5) C₁-C₃ alkoxy,        -   (6) —OCF₃,        -   (7) —NH₂,        -   (8) —OH, or        -   (9) —C≡N;

W is a bond, —S—, —S(O)—, —SO₂—, —O—, —N(R)— where R is hydrogen orC₁-C₄ alkyl;

L is a bond or absent when G is absent, or L is —C(O)—, —S(O)—, —SO₂—,—O—, —C(R₁₁₀)(R₁₁₂)O—, —OC(R₁₁₀)(R₁₁₂)—, —N(R₁₁₀)—, —CON(R₁₁₀)—,—N(R₁₁₀)CO—, —C(R₁₁₀)(R′)—, —C(OH)R₁₁₀—, —SO₂NR₁₁₀—, —N(R₁₁₀)SO₂—,—N(R₁₁₀)CON(R₁₁₂)—, N(R₁₁₀)CSN(R₁₁₂)—, —OCO₂—, —NCO₂—, or —OCON(R₁₁₀)—,where R₁₁₀ and R₁₁₂ are independently hydrogen, or C₁-C₄ alkyl, whereC₁-C₄ alkyl is optionally substituted with OH, C₁-C₄ alkoxy, or one tofive F;

G is absent or:

-   -   (I) C₁-C₁₀ alkyl, optionally substituted with up to three groups        independently selected from        -   (A) —CO₂H,        -   (B) —CO₂(C₁-C₄ alkyl),        -   (C) C₁-C₆ alkoxy,        -   (D) —OH,        -   (E) —NRR′,        -   (F) —C₁-C₆ haloalkyl,        -   (G) —(C₁-C₁₀ alkyl)-O—(C₁-C₃ alkyl),        -   (H) —C₁-C₁₀ alkenyl with one or two double bonds,        -   (I) —C₁-C₁₀ alkynyl with one or two triple bonds,        -   (J) —C₁-C₁₀ alkyl chain with one double bond and one triple            bond,        -   (K) aryl optionally substituted with R₁₀₀,        -   (L) heteroaryl optionally substituted with R₁₀₀,        -   (M) C₁-C₆ alkyl,    -   (II) —(CH₂)₀₋₃—(C₃-C₇) cycloalkyl where cycloalkyl is optionally        substituted with one, two or three substituents selected from        the group consisting of:        -   (A) —O₂H,        -   (B) —CO₂—(C₁-C₄ alkyl),        -   (C) C₁-C₆ alkoxy,        -   (D) —OH,        -   (E) —NH₂,        -   (F) —C₁-C₆ haloalkyl,        -   (G) —(C₁-C₁₀ alkyl)-O—(C₁-C₃ alkyl),        -   (H) —C₁-C₁₀ alkenyl with one or two double bonds,        -   (I) —C₁-C₁₀ alkynyl with one or two triple bonds,        -   (J) —C₁-C₁₀ alkyl chain with one double bond and one triple            bond,        -   (K) aryl optionally substituted with R₁₀₀,        -   (L) heteroaryl optionally substituted with R₁₀₀,        -   (m) mono(C₁-C₆ alkyl)amino, and        -   (n) di(C₁-C₆ alkyl) amino,        -   (o) C₁-C₆ alkyl,    -   (III) —(CRR)₀₋₄-aryl where aryl is optionally substituted with        R₁₀₀,    -   (IV) —(CH₂)₀₋₄-heteroaryl where the heteroaryl is optionally        substituted with one, two, or three independently selected R₁₀₀        groups,    -   (V) —(CH₂)₀₋₄-heterocycle, where the heterocycle is optionally        substituted with one or two R₂₀₀ groups,    -   (VI) —C(R₁₀)(R₁₂)—CO—NH—R₁₋₄ where        -   R₁₀ and R₁₂ are the same or different and are selected from            the group consisting of:        -   (A) —H,        -   (B) —C₁-C₆ alkyl,        -   (C) —(C₁-C₄ alkyl)-aryl, where the aryl is optionally            substituted with one, two, or three independently selected            R₁₀₀ groups,        -   (D) —(C₁-C₄ alkyl)-heteroaryl where the heteroaryl is            optionally substituted with one, two, or three independently            selected R₁₀₀ groups,        -   (E) —(C₁-C₄ alkyl)-heterocycle, where the heterocycle is            optionally substituted with one or two R₂₀₀ groups,        -   (F) heteroaryl where the heteroaryl is optionally            substituted with one, two, or three independently selected            R₁₀₀ groups,        -   (G) heterocycle, where the heterocycle is optionally            substituted with one or two R₂₀₀ groups,        -   (H) —(CH₂)₁₋₄—OH,        -   (I) —(CH₂)₁₋₄—Y—(CH₂)₁₋₄₋aryl where Y is —O—, —S— or            —NR_(C-5)— where R₁₆ is hydrogen or C₁-C₆ alkyl, and where            the aryl is optionally substituted with one, two, or three            independently selected R₁₀₀ groups,        -   (J) —(CH₂)₁₋₄—Y—(CH₂)₁₋₄-heteroaryl where the heteroaryl is            optionally substituted with one, two, or three independently            selected R₁₀₀ groups, and        -   (K) -aryl, where the aryl is optionally substituted with            one, two, or three independently selected R₁₀₀ groups, and        -   R₁₄ is:        -   (A) —H,        -   (B) —C₁-C₆ alkyl,        -   (C) -aryl, where the aryl is optionally substituted with            one, two, or three independently selected R₁₀₀ groups,        -   (D) -heteroaryl where the heteroaryl is optionally            substituted with one, two, or three independently selected            R₁₀₀ groups,        -   (E) -heterocycle, where the heterocycle is optionally            substituted with one or two R₂₀₀ groups,        -   (F) —(C₁-C₄ alkyl)-aryl, where the aryl is optionally            substituted with one, two, or three independently selected            R₁₀₀ groups,        -   (G) —(C₁-C₄ alkyl)-heteroaryl where the heteroaryl is            optionally substituted with one, two, or three independently            selected R₁₀₀ groups,        -   (H) —(C₁-C₄ alkyl)-heterocycle, where the heterocycle is            optionally substituted with one or two R₂₀₀ groups, or        -   (I) —(CH₂)₀₋₂—O—(CH₂)₀₋₂—OH;R₄ and R₅ are independently            hydrogen, halogen, C₁-C₆ alkoxy or C₁-C₄ alkyl.

In yet another method embodiment, R₁ is —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl),or

-   -   C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups        independently selected from halogen, —OH, ═O, —SH, —C≡N, —CF₃,        —C₁-C₃ alkoxy, amino, mono- or dialkylamino, —OC(═O)-amino,        -amino-C(═O)O—, and —OC(═O)-mono- or dialkylamino, or C₁-C₁₀        alkyl optionally substituted —C₁-C₃ alkoxy, or    -   C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionally        substituted with 1, 2, or 3 groups independently selected from        halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or        dialkylamino, or    -   aryl, heteroaryl, heterocyclyl, —C₁-C₆ alkyl-aryl, —C₁-C₆        alkyl-heteroaryl, or —C₁-C₆ alkyl-heterocyclyl, where the ring        portions of each are optionally substituted with 1, 2, 3, or 4        groups independently selected from halogen, —OH, —SH, —C≡N,        —NR₇R′₇, —C(═O)—(C₁-C₄) alkyl, —SO₂-amino, —SO₂-mono or        dialkylamino, —C(═O)-amino, —C(═O)-mono or dialkylamino,        —SO₂—(C₁-C₄) alkyl, or    -   —C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups        which are independently a halogen, or    -   C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groups        independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, amino, —C₁-C₆ alkyl and mono- or dialkylamino, or    -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups        independently selected from halogen, —OH, —SH, —C≡N, —CF₃,        —C₁-C₃ alkoxy, ammo, mono- or dialkylamino and —C₁-C₃ alkyl, or    -   C₂-C₆ alkenyl, alk(di)enyl, C₂-C₆ alkynyl or alk(di)ynyl, each        of which is optionally substituted with 1, 2, or 3 groups        independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, amino, —C₁-C₆ alkyl and mono- or dialkylamino; and the        heterocyclyl group is optionally further substituted with oxo.

In another preferred method embodiment [non-difluorobenzyl embodiment;removal of multiple inactive compounds], R₁ is:

-   -   (I) C₁-C₆ alkyl, optionally substituted with one, two or three        substituents selected from the group consisting of C₁-C₃ alkyl,        C₁-C₇ alkyl (optionally substituted with C₁-C₃ alkyl and C₁-C₃        alkoxy), —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆        alkyl, —OC═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as        defined above,    -   (II) —CH₂—S(O)₀₋₂—(C₁-C₆ alkyl),    -   (III) —CH₂—CH₂—S(O)₀₋₂—(C₁-C₆ alkyl),    -   (IV) C₂-C₆ alkenyl with one or two double bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl,    -   (V) C₂-C₆ alkynyl with one or two triple bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁-C₆ alkyl,    -   (VI) —(CH₂)_(n1)—(R_(1-aryl)) where n₁ is zero or one and where        R_(1-aryl) is phenyl, 1-naphthyl, 2-naphthyl and indanyl,        indenyl, dihydronaphthalyl, tetralinyl optionally substituted        with one, two, three or four of the following substituents on        the aryl ring:        -   (A) C₁-C₆ alkyl optionally substituted with one, two or            three substituents selected from the group consisting of            C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b)            where R_(1-a) and R_(1-b) are as defined above, —C≡N, —CF₃,            C₁-C₃ alkoxy,        -   (B) C₂-C₆ alkenyl with one or two double bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁-C₆ alkyl,        -   (C) C₂-C₆ alkynyl with one or two triple bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁-C₃ alkoxy, —NR_(1-a)R_(1-b)where R_(1-a) and R_(1-b) are            —H or C₁-C₆ alkyl,        -   (D) —Cl, —Br and —I,        -   (F) —C₁-C₆ alkoxy optionally substituted with one, two or            three —F,        -   (G) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as            defined below,        -   (H) —OH,        -   (I) —C≡N,        -   (J) C₃-C₇ cycloalkyl, optionally substituted with one, two            or three substituents selected from the group consisting of            —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,            —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆            alkyl,        -   (K) —CO—(C₁-C₄ alkyl),        -   (L) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above,        -   (M) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above, or        -   (N) —SO₂—(C₁-C₄ alkyl),    -   (VII) —(CH₂)_(n1)—(R_(1-heteroaryl)) where n₁ is as defined        above and where R_(1-heteroaryl) is selected from the group        consisting of:        -   (A) pyridinyl,        -   (B) pyrimidinyl,        -   (C) quinolinyl,        -   (F) benzothienyl,        -   (G) indolyl,        -   (H) indolinyl,        -   (I) pryidazinyl,        -   (J) pyrazinyl,        -   (K) isoindolyl,        -   (L) isoquinolyl,        -   (M) quinazolinyl,        -   (N) quinoxalinyl,        -   (O) phthalazinyl,        -   (P) imidazolyl,        -   (Q) isoxazolyl,        -   (R) pyrazolyl,        -   (S) oxazolyl,        -   (T) thiazolyl,        -   (U) indolizinyl,        -   (V) indazolyl,        -   (W) benzothiazolyl,        -   (X) benzimidazolyl,        -   (Y) benzofuranyl,        -   (Z) furanyl,        -   (AA) thienyl,        -   (BB) pyrrolyl,        -   (CC) oxadiazolyl        -   (DD) thiadiazolyl        -   (EE) triazolyl,        -   (FF) tetrazolyl        -   (II) oxazolopyridinyl,        -   (JJ) imidazopyridinyl        -   (KK) isothiazolyl        -   (LL) naphthyridinyl,        -   (MM) cinnolinyl,        -   (NN) carbazolyl        -   (OO) beta-carbolinyl        -   (PP) isochromanyl        -   (QQ) chromanyl,        -   (SS) tetrahydroisoquinolinyl,        -   (TT) isoindolinyl,        -   (UU) isobenzotetrahydrofuranyl,        -   (VV) isobenzotetrahydrothienyl,        -   (WW) isobenzothienyl,        -   (XX) benzoxazolyl,        -   (YY) pyridopyridinyl,        -   (ZZ) benzotetrahydrofuranyl,        -   (AAA) benzotetrahydrothienyl,        -   (BBB) purinyl,        -   (CCC) benzodioxolyl,        -   (DDD) triazinyl,        -   (EEE) phenoxazinyl,        -   (FFF) phenothiazinyl,        -   (GGG) pteridinyl,        -   (HHH) benzothiazolyl,        -   (III) imidazopyridinyl,        -   (JJJ) imidazothiazolyl,        -   (KKK) dihydrobenzisoxazinyl,        -   (LLL) benzisoxazinyl,        -   (MMM) benzoxazinyl,        -   (NNN) dihydrobenzisothiazinyl,        -   (OOO)benzopyranyl,        -   (PPP) benzothiopyranyl,        -   (QQQ) coumarinyl,        -   (RRR) isocoumarinyl,        -   (SSS) chromonyl,        -   (TTT) chromanonyl, and        -   (UUU) pyridinyl-N-oxide,        -    where the R_(1-heteroaryl) group is bonded to —(CH₂)_(n1)—            by any ring atom of the parent R_(N-heteroaryl) group            substituted by hydrogen such that the new bond to the            R_(1-heteroaryl) group replaces the hydrogen atom and its            bond, where heteroaryl is optionally substituted with one,            two, three or four of:        -   (1) C₁-C₆ alkyl optionally substituted with one, two or            three substituents selected from the group consisting of            C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b)            where R_(1-a) and R_(1-b) are as defined above, —C≡N, —CF₃,            C₁-C₃ alkoxy,        -   (2) C₂-C₆ alkenyl with one or two double bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁-C₆ alkyl,        -   (3) C₂-C₆ alkynyl with one or two triple bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁-C₆ alkyl,        -   (4) —F, Cl, —Br and —I,        -   (6) —C₁-C₆ alkoxy optionally substituted with one, two, or            three —F,        -   (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as            defined below,        -   (8) —OH,        -   (9) —C≡N,        -   (10) C₃-C₇ cycloalkyl, optionally substituted with one, two            or three substituents selected from the group consisting of            —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,            —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆            alkyl,        -   (11) —CO—(C₁-C₄ alkyl),        -   (12) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above,        -   (13) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above, or        -   (14) —SO₂—(C₁-C₄ alkyl), with the proviso that when n₁ is            zero R_(1-heteroaryl) is not bonded to the carbon chain by            nitrogen,    -   (VIII) —(CH₂)_(n1)—(R_(1-heterocycle)) where n₁ is as defined        above and R_(1-heterocycle) is selected from the group        consisting of:        -   (A) morpholinyl,        -   (B) thiomorpholinyl,        -   (C) thiomorpholinyl S-oxide,        -   (D) thiomorpholinyl S,S-dioxide,        -   (E) piperazinyl,        -   (F) homopiperazinyl,        -   (G) pyrrolidinyl,        -   (H) pyrrolinyl,        -   (I) tetrahydropyranyl,        -   (J) piperidinyl,        -   (K) tetrahydrofuranyl,        -   (L) tetrahydrothienyl,        -   (M) homopiperidinyl,        -   (N) homomorpholinyl,        -   (O) homothiomorpholinyl,        -   (P) homomorpholinyl S-oxide,        -   (Q) homothiomorpholinyl S,S-dioxide, and        -   (R) oxazolidinonyl,        -    where the R_(1-heterocycle) group is bonded by any atom of            the parent R_(1-heterocycle) group substituted by hydrogen            such that the new bond to the R_(1-heterocycle) group            replaces the hydrogen atom and its bond, where heterocycle            is optionally substituted with one, two, three or four of:            -   (1) C₁-C₆ alkyl optionally substituted with one, two or                three substituents selected from the group consisting of                C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,                —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as                defined above, —C≡N, —CF₃, C₁-C₃ alkoxy,            -   (2) C₂-C₆ alkenyl with one or two double bonds,                optionally substituted with one, two or three                substituents selected from the group consisting of —F,                —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,                —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or                C₁-C₆ alkyl,            -   (3) C₂-C₆ alkynyl with one or two triple bonds,                optionally substituted with one, two or three                substituents selected from the group consisting of —F,                —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,                —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or                C₁-C₆ alkyl,            -   (4) —F, Cl, —Br and —I,            -   (5) C₁-C₆ alkoxy,            -   (6) —C₁-C₆ alkoxy optionally substituted with one, two,                or three —F,            -   (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as                defined below,            -   (8) —OH,            -   (9) —C≡N,            -   (10) C₃-C₇ cycloalkyl, optionally substituted with one,                two or three substituents selected from the group                consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃                alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are                —H or C₁-C₆ alkyl,            -   (11) —CO—(C₁-C₄ alkyl),            -   (12) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are                as defined above,            -   (13) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are                as defined above,            -   (14) —SO₂—(C₁-C₄ alkyl), or            -   (15) ═O, with the proviso that when n₁ is zero                R_(1-heterocycle) is not bonded to the carbon chain by                nitrogen; or    -   (IX) G-L-A-W-    -   where A is:        -   (I) phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl,            dihydronaphthalyl, tetralinyl, cyclopentyl, cyclohexyl, and            cycloheptyl optionally substituted with one or two of the            following substituents on the ring:        -   (A) —NO₂,        -   (B) —C≡N,        -   (C) —N(R)CO(R′) R, R′ defined below        -   (D) —CO—O—R_(N-5) where R_(N-5) is selected from the group            consisting of:            -   (a) C₁-C₆ alkyl, and            -   (b) —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as                defined above,        -   (E) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,        -   (F) —O—(C₂-C₆ alkyl)-COOH,        -   (G) —NRR′ where R, R′ are H, C₁-C₆ alkyl,            —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as defined above,        -   (H) —SR where R is H, C₁-C₆ alkyl, —(CH₂)₀₋₂—(R_(1-aryl))            where R_(1-aryl) is as defined above,        -   (I) —CH₂OH,        -   (J) —CO—(C₁-C₆) alkyl,        -   (K) —CONRR′ where R, R′ are H, C₁-C₆ alkyl,            —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as defined above,        -   (L) —SO₂NRR′ where R, R′ are H, C₁-C₆ alkyl,        -   (M) —COOH,        -   (N) —C₁-C₆ alkyl,        -   (O) —C₂-C₆ alkenyl with one or two double bonds, or        -   (P) —C₂-C₆ alkynyl with one or two triple bonds,        -   wherein each of (N), (O) and (P) may be optionally            substituted by one to three of —CF₃, —F, —Cl, —Br, —I, C₁-C₃            alkyoxy, —OCF₃, —NH₂, —OH, and —CN, and provided that G, L            and W may not all be absent;        -   (II) R_(1-heteroaryl) as defined above, where the            R_(1-heteroaryl) group bonds to the subsistent W by a ring            carbon atom, and where R_(1-heteroaryl) is optionally            substituted with one, two, three, or four substituents            independently chosen from the group consisting of:        -   (A) —NO₂,        -   (B) —C≡N,        -   (C) —N(R)CO(R′) where R, R′ are defined below,        -   (D) —CO—O—R_(N-5) where R_(N-5) is selected from the group            consisting of:            -   (a) C₁-C₆ alkyl, and            -   (b) —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as                defined above,        -   (E) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,        -   (F) —O—(C₂-C₆ alkyl)-COOH,        -   (G) —NRR′ where R, R′ are independently H, C₁-C₆ alkyl, and            —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as defined above,        -   (H) —SR where R and R_(1-aryl) are as defined above,        -   (I) —CH₂OH,        -   (J) —CO—(C₁-C₆) alkyl,        -   (K) —CONRR′ where R, R′ and R_(1-aryl) are as defined above,        -   (L) —SO₂NRR′ where R, R′ are H, C₁-C₆ alkyl,        -   (M) —COOH,        -   (N) —C₁-C₆ alkyl,        -   (O) —C₂-C₆ alkenyl with one or two double bonds, and        -   (P) —C₂-C₆ alkynyl with one or two triple bonds,        -   wherein each of (N), (O) and (P) may be optionally            substituted by one to three substituent indepedendly chosen            from the group consisting of —CF₃, —F, —Cl, —Br, —I, C₁-C₃            alkyoxy, —OCF₃, —NH₂, —OH, and —CN, and provided that G, L            and W may not all be absent, or        -   (III) R_(1-heterocycle) as defined above:

where the R_(1-heterocycle) group bonds to the subsistent W by a ringcarbon atom, and where R_(1-heteroaryl) is optionally substituted withone to two substituents independently chosen from the group consistingof

-   -   -   (1) ═O,        -   (2) C₁-C₃ alkyl,        -   (3) —CF₃,        -   (4) —F, Cl, —Br or —I,        -   (5) C₁-C₃ alkoxy,        -   (6) —O—CF₃,        -   (7) —NH₂,        -   (8) —OH, and        -   (9) —C≡N,

and provided that G, L and W may not all be absent,

where W is —S(O)₀₋₂—, —O—, —N—, or absent, and N is optionallysubstituted with C₁-C₄ alkyl;

where L is —CO—, —S(O)₁₋₂—, —O—, —C(Ra)(Rb)O—, —OC(Ra)(Rb)—, —N(Ra)—,—CON(Ra)—, —N(Ra)CO—, —C(Ra)(Rb)—, —C(OH)Ra—, —SO₂NRa—, —N(Ra)SO₂—,—N(Ra)CON(Rb)—, N(Ra)CSN(Rb)—, —OCOO—, —NCOO—, OCON(Ra)—, a bond, or Lis absent when G is absent, and where Ra and Rb are independently H,C₁-C₄ alkyl which are optionally substituted. with OH, C₁-C₄ alkoxy, andup to five —F;

-   -   where G is:    -   (I) —C₁-C₁₀ alkyl optionally substituted with one substituent        selected from the group consisting of:        -   (A) —COOH,        -   (B) —CO—O—(C₁-C₄ alkyl),        -   (C) C₁-C₆ alkoxy,        -   (D) —OH,        -   (E) —NH₂,        -   (F) —C₁-C₆ alkyl optionally substituted with one to five —F        -   (G) —(C₁-C₁₀ alkyl)-O—(C₁-C₃ alkyl),        -   (H) —C₂-C₁₀ alkenyl with one or two double bonds,        -   (I) —C₂-C₁₀ alkynyl with one or two triple bonds,        -   (J) —C₄-C₁₀ hydrocarbyl chain with one double bond and one            triple bond,        -   (K) —R_(1-aryl) where R_(1-aryl) is as defined above,        -   (L) —R_(1-heteroaryl) where R_(1-heteroaryl) is as defined            above,    -   (II) —(CH₂)₀₋₃—(C₃-C₇) cycloalkyl where cycloalkyl can be        optionally substituted with one, two or three substituents        selected from the group consisting of:        -   (A) —COOH,        -   (B) —CO—O—(C₁-C₄ alkyl),        -   (C) C₁-C₆ alkoxy,        -   (D) —OH,        -   (E) —NH₂,        -   (F) —C₁-C₆ alkyl optionally substituted with one to five —F        -   (G) —(C₁-C₁₀ alkyl)-O—(C₁-C₃ alkyl),        -   (H) —C₂-C₁₀ alkenyl with one or two double bonds,        -   (I) —C₂-C₁₀ alkynyl with one or two triple bonds,        -   (J) —C₄-C₁₀ hydrocarbyl chain with one double bond and one            triple bond,        -   (K) —R_(1-aryl) where R_(1-aryl) is as defined above,        -   (L) —R_(1-heteroaryl) where R_(1-heteroaryl) is as defined            above,    -   (III) —(CR′R″)₀₋₄—R_(1-aryl) where R′, R″ and R_(1-aryl) are as        defined above,    -   (IV) —(CH₂)₀₋₄—R_(1-heteroaryl) where R_(1-heteroaryl) is as        defined above,    -   (V) —(CH₂)₀₋₄—R_(1-heterocycle) where R_(1-heterocycle) is as        defined above,    -   (VI) —C(R_(C-1))(R_(C-2))—CO—NH—R_(C-3) where R_(C-1) and        —R_(C-2) are independently selected from the group consisting        of:        -   (A) —H,        -   (B) —C₁-C₆ alkyl,        -   (C) —(C₀-C₄ alkyl)-R_(1-aryl), wherein R_(1-aryl) is as            defined above,        -   (D) —(C₀-C₄ alkyl)-R_(1-heteroaryl), wherein            R_(1-heteroaryl) is as defined above,        -   (E) —(C₀-C₄ alkyl)-R_(1-heterocycle), wherein            R_(1-heterocycle) is as defined above,        -   (F) —(CH₂)₁₋₄—OH,        -   (G) —(CH₂)₁₋₄—R_(C-4)—(CH₂)₁₋₄—R_(C′-aryl) where —R_(C-4) is            —O—, —S— or        -   (H) —NR_(C-5)— where R_(C-5) is — or C₁-C₆ alkyl, and where            R_(C′-aryl) is defined above, and        -   (I) —(CH₂)₁₋₄—R_(C-4)—(CH₂)₁₋₄—R_(C-heteroaryl) where            —R_(C-4) and R_(C-heteroaryl) are as defined above,        -   wherein in (C), (D) and (E) C₀ is merely a bond, and where            R_(C-3) is:            -   (a) —H,            -   (b) —C₁-C₆ alkyl,            -   (c) —(C₀-C₄ alkyl)-R_(1-aryl) where R_(1-aryl) is as                defined above,            -   (d) —(C₀-C₄ alkyl)-R_(1-heteroaryl) where                R_(1-hetroaryl) is as defined above,            -   (e) —(C₀-C₄ alkyl)-R_(1-heterocycle) where                R_(1-heterocycle) is as defined above,    -   (VII) -cyclopentyl or -cyclohexyl ring fused to a phenyl or        heteroaryl ring where heteroaryl is as defined above and phenyl        and heteroaryl are optionally substituted with one, two or three        of:        -   (D) C₁-C₆ alkyl,        -   (B) —CF₃,        -   (C) —F, Cl, —Br and —I,        -   (D) C₁-C₃ alkoxy,        -   (E) —OCF₃,        -   (F) —NH₂,        -   (G) —OH,        -   (H) —C≡N,        -   (I) —NO₂        -   (J) —CO—OH,        -   (K) —CO—O—R_(N-5) where R_(N-5) is selected from the group            consisting of:            -   (a) C₁-C₆ alkyl, and            -   (b) —(C₀-C₂ alkyl)-(R_(1-aryl)) where R_(1-aryl) is as                defined above,        -   (L) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,        -   (M) —O—(C₂-C₅ alkyl)-COOH, or        -   (N) —OR where R is as defined above,        -   (O) —NR—R′ where R and R′ are as defined above,        -   (P) —SR where R is as defined above,        -   (Q) —CF₃,        -   (R) —OCF₃,        -   (S) —N(R)COR′ where R, R′ are as defined above,        -   (T) —NRR′ where R, R′ are as defined above,        -   (U) —SR where R is as defined above,        -   (V) —CH₂OH,        -   (W) —CO—(C₁-C₆) alkyl,        -   (X) —CONRR′ where R, R′ are as defined above, or        -   (Y) —SO₂NRR′ where R is as defined above, or    -   (VIII) —(CH₂)₂—O—(CH₂)₂—OH.

In yet another preferred method embodiment [non-phenyl embodiment;removal of multiple inactive compounds], Rc is selected from the groupconsisting of C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from the group consisting of R₂₀₅, —OC═ONR₂₃₅R₂₄₀, —S(═O)₀₋₂ R₂₃₅, —NR₂₃₅C═O NR₂₃₅R₂₄₀, —C═O NR₂₃₅R₂₄₀, and—S(═O)₂ NR₂₃₅R₂₄₀; —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl wherein the cycloalkylis optionally substituted with 1, 2, or 3 groups independently selectedfrom the group consisting of R₂₀₅, —CO₂H, and —CO₂—(C₁-C₄ alkyl);—(CR₂₄₅R₂₅₀)₁₋₄-aryl; —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl,—(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl; —(CR₂₄₅R₂₅₀)₀₋₄-aryl-heteroaryl;—(CR₂₄₅R₂₅₀)₀₋₄-aryl-heterocycloalkyl; —(CR₂₄₅R₂₅₀)₀₋₄-aryl-aryl;—(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-aryl;—(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heterocycloalkyl;—(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heteroaryl;—(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-heteroaryl;—(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-heterocycloalkyl;—(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-aryl; —[C(R₂₅₅)(R₂₆₀)]₁₋₃—CO—N—(R₂₅₅)₂;—CH(aryl)₂; —CH(heteroaryl)₂; —CH(heterocycloalkyl)₂;—CH(aryl)(heteroaryl); cyclopentyl, cyclohexyl, or cycloheptyl ringfused to aryl, heteroaryl, or heterocycloalkyl wherein one carbon of thecyclopentyl, cyclohexyl, or cycloheptyl is optionally replaced with oneor two NH, NR₂₁₅, O, or S(═O)₀₋₂, and wherein the cyclopentylcyclohexyl, or cycloheptyl group can be optionally substituted with 1 or2 groups that are independently R₂₀₅, ═O, —CO—NR₂₃₅R₂₄₀, or —SO₂—(C₁-C₄alkyl); C₂-C₁₀ alkenyl optionally substituted with 1, 2, or 3 R₂₀₅groups; C₂-C₁₀ alkynyl optionally substituted with 1, 2, or 3 R₂₀₅groups; —(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH)—(CH₂)₀₋₁-aryl;—(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH—(CH₂)₀₋₁-heteroaryl; —CH(-aryl or-heteroaryl)-CO—O(C₁-C₄ alkyl); —CH(—CH₂—OH)—CH(OH)-phenyl-NO₂; (C₁-C₆alkyl)-O—(C₁-C₆ alkyl)-OH; —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂; —H; and—(CH₂)₀₋₆—C(═NR₂₃₅)(NR₂₃₅R₂₄₀); wherein

-   each aryl is optionally substituted with 1, 2, or 3 R₂₀₀;-   each heteroaryl is optionally substituted with 1, 2, 3, or 4 R₂₀₀;-   each heterocycloalkyl is optionally substituted with 1, 2, 3, or 4    R₂₁₀;-   R₂₀₀ at each occurrence is independently selected from the group    consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; OH; —NO₂; halogen; —CO₂H; C≡N; —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅;    —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl); —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl);    —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl); —(CH₂)₀₋₄—CO—(C₃-C₇ cycloalkyl);    —(CH₂)₀₋₄—CO-aryl; —(CH₂)₀₋₄—CO-heteroaryl;    —(CH₂)₀₋₄—CO-heterocycloalkyl; —(CH₂)₀₋₄—CO—O—R₂₁₅;    —(CH₂)₀₋₄—SO₂—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl);    —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl); —(CH₂)₀₋₄—SO₂—(C₃-C₇ cycloalkyl);    —(CH₂)₀₋₄—N(H or R₂₁₅)—CO—O—R₂₁₅; —(CH₂)₀₋₄—N(H or    R₂₁₅)—CO—N(R₂₁₅)₂; —(CH₂)₀₋₄—N—CS—N(R₂₁₅)₂; —(CH₂)₀₋₄—N(—H or    R₂₁₅)—CO—R₂₂₀; —(CH₂)₀₋₄—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl);    —(CH₂)₀₋₄—O—P(O)—(OR₂₄₀)₂; —(CH₂)₀₋₄—O—CO—N(R₂₁₅)₂;    —(CH₂)₀₋₄—O—CS—N(R₂₁₅)₂; —(CH₂)₀₋₄—O—(R₂₁₅);    —(CH₂)₀₋₄—O—(R₂₁₅)—COOH; —(CH₂)₀₋₄—S—(R₂₁₅); —(CH₂)₀₋₄—O—(C₁-C₆    alkyl optionally substituted with 1, 2, 3, or 5 —F); C₃-C₇    cycloalkyl; C₂-C₆ alkenyl optionally substituted with 1 or 2 R₂₀₅    groups; C₂-C₆ alkynyl optionally substituted with 1 or 2 R₂₀₅    groups; —(CH₂)₀₋₄—N(H or R₂₁₅)—SO₂—R₂₂₀; and —(CH₂)₀₋₄—C₃-C₇    cycloalkyl;    -   wherein each aryl group at each occurrence is optionally        substituted with 1, 2, or 3 groups that are independently R₂₀₅,        R₂₁₀ or C₁-C₆ alkyl substituted with 1, 2, or 3 groups that are        independently R₂₀₅ or R₂₁₀;    -   wherein each heterocycloalkyl group at each occurrence is        optionally substituted with 1, 2, or 3 groups that are        independently R₂₁₀;    -   wherein each heteroaryl group at each occurrence is optionally        substituted with 1, 2, or 3 groups that are independently R₂₀₅,        R₂₁₀, or C₁-C₆ alkyl substituted with 1, 2, or 3 groups that are        independently R₂₀₅ or R₂₁₀;-   R₂₀₅ at each occurrence is independently selected from the group    consisting of C₁-C₆ alkyl, halogen, —OH, —O-phenyl, —SH, —C≡N, —CF₃,    C₁-C₆ alkoxy, NH₂, NH(C₁-C₆ alkyl), and N—(C₁-C₆ alkyl)(C₁-C₆    alkyl);-   R₂₁₀ at each occurrence is independently selected from the group    consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; C₂-C₆ alkenyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; C₂-C₆ alkynyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; halogen; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy, —NR₂₂₀R₂₂₅;    OH; C≡N; C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; —CO—(C₁-C₄ alkyl); _SO_(2—)NR₂₃₅R₂₄₀; —CO—NR₂₃₅R₂₄₀;    —SO₂—(C₁-C₄ alkyl); and ═O;-   R₂₁₅ at each occurrence is independently selected from the group    consisting of C₁-C₆ alkyl, —(CH₂)₀₋₂-(aryl), C₂-C₆ alkenyl, C₂-C₆    alkynyl, C₃-C₇ cycloalkyl, and —(CH₂)₀₋₂-(heteroaryl),    —(CH₂)₀₋₂-(heterocycloalkyl); wherein the aryl group at each    occurrence is optionally substituted with 1, 2, or 3 groups that are    independently R₂₀₅ or R₂₁₀; wherein the heterocycloalkyl group at    each occurrence is optionally substituted with 1, 2, or 3 R₂₁₀;    wherein each heteroaryl group at each occurrence is optionally    substituted with 1, 2, or 3 R₂₁₀;    -   R₂₂₀ and R₂₂₅ at each occurrence are independently selected from        the group consisting of —H, —C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl,        amino C₁-C₆ alkyl; halo C₁-C₆ alkyl; —C₃-C₇ cycloalkyl, —(C₁-C₂        alkyl)-(C₃-C₇ cycloalkyl), —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl),        —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₁-C₆ alkyl chain with one        double bond and one triple bond, -aryl, -heteroaryl, and        -heterocycloalkyl;        -   wherein the aryl group at each occurrence is optionally            substituted with 1, 2, or 3 groups that are independently            R₂₀₅ or R₂₁₀;        -   wherein the heterocycloalkyl group at each occurrence is            optionally substituted with 1, 2, or 3 R₂₁₀;        -   wherein each heteroaryl group at each occurrence is            optionally substituted with 1, 2, or 3 R₂₁₀;-   R₂₃₅ and R₂₄₀ at each occurrence are independently H, or C₁-C₆    alkyl;-   R₂₄₅ and R₂₅₀ at each occurrence are independently selected from the    group consisting of H, C₁-C₄ alkyl, C₁-C₄ alkylaryl, C₁-C₄    alkylheteroaryl, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy,    —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and    phenyl; or    R₂₄₅ and R₂₅₀ are taken together with the carbon to which they are    attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon atoms,    optionally where one carbon atom is replaced by a heteroatom    selected from the group consisting of —O—, —S—, —SO₂—, and —NR₂₂₀—;-   R₂₅₅ and R₂₆₀ at each occurrence are independently selected from the    group consisting of H; C₁-C₆ alkyl optionally substituted with 1, 2,    or 3 R₂₀₅ groups; C₂-C₆ alkenyl optionally substituted with 1, 2, or    3 R₂₀₅ groups; C₂-C₆ alkynyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl); —(CH₂)₀₋₄—C₃-C₇    cycloalkyl optionally substituted with 1, 2, or 3 R₂₀₅ groups;    —(C₁-C₄ alkyl)-aryl; —(C₁-C₄ alkyl)-heteroaryl; —(C₁-C₄    alkyl)-heterocycloalkyl; -aryl; -heteroaryl; -heterocycloalkyl;    _(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-aryl; —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heteroaryl;    and; —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heterocycloalkyl; wherein    -   R₂₆₅ at each occurrence is independently —O—, —S— or —N(C₁-C₆        alkyl)-;    -   each aryl or phenyl is optionally substituted with 1, 2, or 3        groups that are independently R₂₀₅, R₂₁₀, or C₁-C₆ alkyl        substituted with 1, 2, or 3 groups that are independently R₂₀₅        or R₂₁₀;    -   each heteroaryl is optionally substituted with 1, 2, 3, or 4        R₂₀₀,    -   each heterocycloalkyl is optionally substituted with 1, 2, 3, or        4 R₂₁₀.

In a further preferred method embodiment [non-CH₂-phenyl embodiment;removal of multiple inactive compounds], Rc is selected from the groupconsisting of C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from the group consisting of R₂₀₅, —OC═ONR₂₃₅R₂₄₀, —S(═O)₀₋₂ R₂₃₅, —NR₂₃₅C═O NR₂₃₅R₂₄₀, —C═O NR₂₃₅R₂₄₀, and—S(═O)₂ NR₂₃₅R₂₄₀; —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl wherein the cycloalkylis optionally substituted with 1, 2, or 3 groups independently selectedfrom the group consisting of R₂₀₅, —CO₂H, and —CO₂—(C₁-C₄ alkyl);—(CR₂₄₅R₂₅₀)₂₋₄-aryl; —(CR₂₄₅R₂₅₀)₀₋₄—heteroaryl,—(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl; —(CR₂₄₅R₂₅₀)₀₋₄-aryl-heteroaryl;—(CR₂₄₅R₂₅₀)₀₋₄-aryl-heterocycloalkyl; —(CR₂₄₅R₂₅₀)₀₋₄-aryl-aryl;—(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-aryl;—(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heterocycloalkyl;—(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heteroaryl;—(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-heteroaryl;—(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-heterocycloalkyl;—(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-aryl; —[C(R₂₅₅)(R₂₆₀)]₁₋₃—CO—N—(R₂₅₅)₂;—CH(aryl)₂; —CH(heteroaryl)₂; —CH(heterocycloalkyl)₂;—CH(aryl)(heteroaryl); cyclopentyl, cyclohexyl, or cycloheptyl ringfused to aryl, heteroaryl, or heterocycloalkyl wherein one carbon of thecyclopentyl, cyclohexyl, or cycloheptyl is optionally replaced with oneor two NH, NR₂₁₅, O, or S(═O)₀₋₂, and wherein the cyclopentyl,cyclohexyl, or cycloheptyl group can be optionally substituted with 1 or2 groups that are independently R₂₀₅, ═O, —CO—NR₂₃₅R₂₄₀, or —SO₂—(C₁-C₄alkyl); C₂-C₁₀ alkenyl optionally substituted with 1, 2, or 3 R₂₀₅groups; C₂-C₁₀ alkynyl optionally substituted with 1, 2, or 3 R₂₀₅groups; —(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH)—(CH₂)₀₋₁-aryl;—(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH—(CH₂)₀₋₁-heteroaryl; —CH(-aryl or-heteroaryl)-CO—O(C₁-C₄ alkyl); —CH(—CH₂—OH)—CH(OH)-phenyl-NO₂; (C₁-C₆alkyl)-O—(C₁-C₆ alkyl)-OH; —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂; —H; and—(CH₂)₀₋₆—C(═NR₂₃₅)(NR₂₃₅R₂₄₀); wherein

-   each aryl is optionally substituted with 1, 2, or 3 R₂₀₀;-   each heteroaryl is optionally substituted with 1, 2, 3, or 4 R₂₀₀;-   each heterocycloalkyl is optionally substituted with 1, 2, 3, or 4    R₂₁₀;-   R₂₀₀ at each occurrence is independently selected from the group    consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; OH; —NO₂; halogen; —CO₂H; C≡N; —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅;    —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl); —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl);    —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl); —(CH₂)₀₋₄—CO—(C₃-C₇ cycloalkyl);    —(CH₂)₀₋₄—CO-aryl; —(CH₂)₀₋₄—CO-heteroaryl;    —(CH₂)₀₋₄—CO-heterocycloalkyl; —(CH₂)₀₋₄—CO—O—R₂₁₅;    —(CH₂)₀₋₄—SO₂—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl);    —(CH₂)₀₋₄—SO_(2—)(C₁-C₁₂ alkyl); —(CH₂)₀₋₄—SO₂—(C₃-C₇ cycloalkyl);    —(CH₂)₀₋₄—N(H or R₂₁₅)—CO—O—R₂₁₅; —(CH₂)₀₋₄—N(H or    R₂₁₅)—CO—N(R₂₁₅)₂; —(CH₂)₀₋₄—N—CS—N(R₂₁₅)₂; —(CH₂)₀₋₄—N(—H or    R₂₁₅)—CO—R₂₂₀; —(CH₂)₀₋₄—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl);    —(CH₂)₀₋₄—O—P(O)—(OR₂₄₀)₂; —(CH₂)₀₋₄—O—CO—N(R₂₁₅)₂;    —(CH₂)₀₋₄—O—CS—N(R₂₁₅)₂; —(CH₂)₀₋₄—O—(R₂₁₅);    —(CH₂)₀₋₄—O—(R₂₁₅)—COOH; —(CH₂)₀₋₄—S—(R₂₁₅); —(CH₂)₀₋₄—O—(C₁-C₆    alkyl optionally substituted with 1, 2, 3, or 5 —F); C₃-C₇    cycloalkyl; C₂-C₆ alkenyl optionally substituted with 1 or 2 R₂₀₅    groups; C₂-C₆ alkynyl optionally substituted with 1 or 2 R₂₀₅    groups; —(CH₂)₀₋₄—N(H or R₂₁₅)—SO₂—R₂₂₀; and —(CH₂)₀₋₄—C₃-C₇    cycloalkyl;    -   wherein each aryl group at each occurrence is optionally        substituted with 1, 2, or 3 groups that are independently R₂₀₅,        R₂₁₀ or C₁-C₆ alkyl substituted with 1, 2, or 3 groups that are        independently R₂₀₅ or R₂₁₀;    -   wherein each heterocycloalkyl group at each occurrence is        optionally substituted with 1, 2, or 3 groups that are        independently R₂₁₀;    -   wherein each heteroaryl group at each occurrence is optionally        substituted with 1, 2, or 3 groups that are independently R₂₀₅,        R₂₁₀, or C₁-C₆ alkyl substituted with 1, 2, or 3 groups that are        independently R₂₀₅ or R₂₁₀;-   R₂₀₅ at each occurrence is independently selected from the group    consisting of C₁-C₆ alkyl, halogen, —OH, —O-phenyl, —SH, —C≡N, —CF₃,    C₁-C₆ alkoxy, NH₂, NH(C₁-C₆ alkyl), and N—(C₁-C₆ alkyl)(C₁-C₆    alkyl);-   R₂₁₀ at each occurrence is independently selected from the group    consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; C₂-C₆ alkenyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; C₂-C₆ alkynyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; halogen; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; —NR₂₂₀R₂₂₅;    OH; C≡N; C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; —CO—(C₁-C₄ alkyl); _SO_(2—)NR₂₃₅R₂₄₀; —CO—NR₂₃₅R₂₄₀;    —SO₂—(C₁-C₄ alkyl); and ═O;-   R₂₁₅ at each occurrence is independently selected from the group    consisting of C₁-C₆ alkyl, —(CH₂)₀₋₂-(aryl), C₂-C₆ alkenyl, C₂-C₆    alkynyl, C₃-C₇ cycloalkyl, and —(CH₂)₀₋₂-(heteroaryl),    —(CH₂)₀₋₂-(heterocycloalkyl); wherein the aryl group at each    occurrence is optionally substituted with 1, 2, or 3 groups that are    independently R₂₀₅ or R₂₁₀; wherein the heterocycloalkyl group at    each occurrence is optionally substituted with 1, 2, or 3 R₂₁₀;    wherein each heteroaryl group at each occurrence is optionally    substituted with 1, 2, or 3 R₂₁₀;    -   R₂₂₀ and R₂₂₅ at each occurrence are independently selected from        the group consisting of —H, —C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl,        amino C₁-C₆ alkyl; halo C₁-C₆ alkyl; —C₃-C₇ cycloalkyl, —(C₁-C₂        alkyl)-(C₃-C₇ cycloalkyl), —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl),        —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₁-C₆ alkyl chain with one        double bond and one triple bond, -aryl, -heteroaryl, and        -heterocycloalkyl;        -   wherein the aryl group at each occurrence is optionally            substituted with 1, 2, or 3 groups that are independently            R₂₀₅ or R₂₁₀;        -   wherein the heterocycloalkyl group at each occurrence is            optionally substituted with 1, 2, or 3 R₂₁₀;        -   wherein each heteroaryl group at each occurrence is            optionally substituted with 1, 2, or 3 R₂₁₀;-   R₂₃₅ and R₂₄₀ at each occurrence are independently H, or C₁-C₆    alkyl;-   R₂₄₅ and R₂₅₀ at each occurrence are independently selected from the    group consisting of H, C₁-C₄ alkyl, C₁-C₄ alkylaryl, C₁-C₄    alkylheteroaryl, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy,    —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and    phenyl; or    R₂₄₅ and R₂₅₀ are taken together with the carbon to which they are    attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon atoms,    optionally where one carbon atom is replaced by a heteroatom    selected from the group consisting of —O—, —S—, —SO₂—, and —NR₂₂₀—;-   R₂₅₅ and R₂₆₀ at each occurrence are independently selected from the    group consisting of H; C₁-C₆ alkyl optionally substituted with 1, 2,    or 3 R₂₀₅ groups; C₂-C₆ alkenyl optionally substituted with 1, 2, or    3 R₂₀₅ groups; C₂-C₆ alkynyl optionally substituted with 1, 2, or 3    R₂₀₅ groups; —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl); —(CH₂)₀₋₄—C₃-C₇    cycloalkyl optionally substituted with 1, 2, or 3 R₂₀₅ groups;    —(C₁-C₄ alkyl)-aryl; —(C₁-C₄ alkyl)-heteroaryl; —(C₁-C₄    alkyl)-heterocycloalkyl; -aryl; -heteroaryl; -heterocycloalkyl;    _(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-aryl; —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heteroaryl;    and; —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heterocycloalkyl; wherein    -   R₂₆₅ at each occurrence is independently —O—, —S— or —N(C₁-C₆        alkyl)-;    -   each aryl or phenyl is optionally substituted with 1, 2, or 3        groups that are independently R₂₀₅, R₂₁₀, or C₁-C₆ alkyl        substituted with 1, 2, or 3 groups that are independently R₂₀₅        or R₂₁₀;    -   each heteroaryl is optionally substituted with 1, 2, 3, or 4        R₂₀₀,    -   each heterocycloalkyl is optionally substituted with 1, 2, 3, or        4 R₂₁₀.

In a preferred embodiment, the invention encompasses a method oftreating a patient who has, or in preventing a patient from getting, adisease or condition selected from the group consisting of Alzheimer'sdisease, for helping prevent or delay the onset of Alzheimer's disease,for treating patients with mild cognitive impairment (MCI) andpreventing or delaying the onset of Alzheimer's disease in those whowould progress from MCI to AD, for treating Down's syndrome, fortreating humans who have Hereditary Cerebral Hemorrhage with Amyloidosisof the Dutch-Type, for treating cerebral amyloid angiopathy andpreventing its potential consequences, i.e. single and recurrent lobarhemorrhages, for treating other degenerative dementias, includingdementias of mixed vascular and degenerative origin, dementia associatedwith Parkinson's disease, dementia associated with progressivesupranuclear palsy, dementia associated with cortical basaldegeneration, diffuse Lewy body type of Alzheimer's disease and who isin need of such treatment which comprises administration of atherapeutically effective amount of a compound selected from the groupconsisting of a substituted aminoalcohol of the formula (I):

or a pharmaceutically acceptable salt or ester thereof, wherein B is Hor C₁-C₁₀ straight or branched chain alkyl; R₂₀, R₂ and R₃ are H; n is0; R₁ is 3,5-difluorophenyl; and Rc is

where R is a C₁-C₄ straight or branched chain alkyl group, optionallysubstituted with —OB or —SO₂B.

The invention provides compounds of formula (I) that are useful intreating and preventing Alzheimer's disease. The anti-Alzheimer'scompounds of formula (I) are made by methods well known to those skilledin the art from starting compounds known to those skilled in the art.The process chemistry is well known to those skilled in the art. Thecompounds of formula (I) or portions thereof may be prepared the avariety synthetic pathways. The most general process to prepare thecompounds of formula (I) is set forth in Scheme I below.

The chemistry is straight forward and in summary involves the steps ofN-protecting an amino acid (I) starting material to produce thecorresponding protected amino acid, coupling of the protected amino acidwith methoxymethylamine using an amide-bond-forming coupling agent suchas EDC, followed by reaction of the resulting activated amide, known asa Weinreb amide, with a Grignard reagent to form the protected aminoketone. Reduction of the protected aminoketone to the correspondingalcohol via a hydride reduction, using a mild reducing agent such asNaBH₄ (sodium borohydride), One skilled in the art will appreciate thatthese are all well-known reactions in organic chemistry. A chemistskilled in the ark knowing the chemical structure of the biologicallyactive substituted aminoalcohol end product (I) of the invention wouldbe able to prepare them by known methods from known starting materialswithout any additional information.

Scheme I sets forth a general method used in the invention to preparethe compounds of formula (I). The anti-Alzheimer compounds of formula(I) are prepared by starting with the appropriately selected amino acidhaving the desired alpha substituent. The amino acids are well known tothose skilled in the art and/or can be readily prepared from knowncompounds by methods well known to those skilled in the art. Naturalamino acids (and having the L configuration) are available in abundance,and a great array of non-naturally occurring amino acids have beenprepared by techniques well known to those skilled in the art of organicsynthesis or are available commercially. Roberts and Vellaccio provide acomprehensive listing of non-natural amino acids, and techniques for thesynthesis of many variations thereof in The Peptides, Vol. 5: Analysis,Synthesis, Biology; Academic Press, NY 1983. A more recent descriptionof additional routes to chirally pure non-natural amino acids is in:Asymmetric synthesis of α-amino acids from carbohydrates as chiraltemplates; Cintas, P., Tetrahedron, 47 (32), 6079-111 (1991). Thus oneskilled in the art can synthesize the amino acid precursors used in thepreparation of the compounds of the invention by a judicious selectionof one or more of the methods outlined above, which articles are herebyincorporated by reference. Alternatively, many amino acid derivedcompounds may advantageously be purchased commercially. Such amino acidderivatives are available having a wide variety of alpha substituents.Such derivatives are available, by way of example from Synthetech, Inc.(1290 Industrial Way, P. O. Box 646, Albany, Oreg. 97321 USA), whichpublishes catalogs of available compounds.

The compounds of formula (I) have at least two enantiomeric centerswhich give four enantiomers. The first of these enantiomeric centersderives from the amino acid starting material (I). It is preferred tocommercially obtain or produce the desired enantiomer (S) rather thanproduce an enantiomerically impure mixture and then have to separate outthe desired enantiomer (S). It is preferred to start the process withenantiomerically pure (S)-amino acid of the same configuration as thatof the substituted aminoalcohol (I) product.

The first step of the process is to protect the free amino group of the(S)-amino acid (I) with an amino protecting group to produce the(S)-protected amino acid (II) by methods well known to those skilled inthe art. Amino protecting groups are well known to those skilled in theart. See for example, “Protecting Groups in Organic Synthesis”, JohnWiley and sons, New York, N.Y., 1981, Chapter 7; “Protecting Groups inOrganic Chemistry”, Plenum Press, New York, N.Y., 1973, Chapter 2. Thefunction of the amino protecting group is to protect the free aminofunctionality (—NH₂) during subsequent reactions on the (S)-amino acid(I) which would not proceed well either because the amino group wouldreact and be functionalized in a way that is inconsistent with its needto be free for subsequent reactions or the free amino group wouldinterfere in the reaction. When the amino protecting group is no longerneeded, it is removed by methods well known to those skilled in the art.By definition the amino protecting group must be readily removable as isknown to those skilled in the art by methods well known to those skilledin the art. Suitable amino protecting group is selected from the groupconsisting of t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl,acetyl, trichloroacetyl, dichloroacetyl, chloroacetyl, trifluoroacetyl,difluoroacetyl, fluoroacetyl, 4-phenylbenzyloxycarbonyl,2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl,4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl,1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl,2-phenylprop-2-yloxycarbonyl, 2-p-toluyl)prop-2-yloxycarbonyl,cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl,cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycabonyl,2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl,2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl,fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,isobornyloxycarbonyl and 1-piperidyloxycarbonyl, 9-fluorenylmethylcarbonate, —CH—CH═CH₂ and phenyl-C(═N—)—H. It is preferred that theprotecting group be t-butoxycarbonyl (BOC) and benzyloxycarbony (CBZ),it is more preferred that the protecting group be t-butoxycarbonyl. Oneskilled in the art will understand the preferred methods of introducinga t-butoxycarbonyl or benzyloxycarbonyl protecting group and mayadditionally consult T. W. Green and P. G. M. Wuts in “protective Groupsin Organic Chemistry,” John Wiley and Sons, 1991 for guidance.

Suitable means for removal of the amine protecting group depends on thenature of the protecting group. Those skilled in the art, knowing thenature of a specific protecting group, know which reagent is preferablefor its removal. For example, it is preferred to remove the preferredprotecting group, BOC, by dissolving the (SR)-protected alcohol (VII) ina trifluoroacetic acid/dichloromethane mixture. When complete, thesolvents are removed under reduced pressure to give the corresponding(S,R)-amine (as the corresponding salt, i.e. trifluoroacetic acid salt)which is used without further purification. However, if desired, the(S,R)-amine can be purified further by means well known to those skilledin the art, such as for example, recrystallization, or by HPLCpurification optionally using chiral-selective solid supports. Further,if the non-salt form is desired that also can be obtained by means knownto those skilled in the art, such as for example, preparing the freebase amine via treatment of the salt with mild basic conditions.Additional BOC deprotection conditions and deprotection conditions forother protecting groups can be found in T. W. Green and P. G. M. Wuts in“Protective Groups in Organic Chemistry,” John Wiley and Sons, 1991, p.309. Typical chemically suitable salts include trifluoroacetate, and theanion of mineral acids such as chloride, sulfate, phosphate; preferredis trifluoroacetate and chloride.

Many Grignard reagents are available for purchase; others are preparedby methods known to those skilled in the art. The Grignard reagents arethen applied in the method for preparing the amino ketone intermediatesby preparation of the Weinreb amide, either from the acid directly asdepicted in Scheme I or by way of acid halide followed by treatment withN,O-dimethylhydroxylamine to give Weinreb amide and then treating theWeinreb amide with the Grignard reagent, by methods known to thoseskilled in the art.

The compounds of the invention may contain geometric or optical isomersas well as tautomers. Thus, the invention includes all tautomers andpure geometric isomers, such as the E and Z geometric isomers, as wellas mixtures thereof. Futhermore, the invention includes pure enantiomersand diasteriomers as well as mixtures thereof, including racemicmixtures. The individual geometric isomers, enantiomers, ordiasteriomers may be prepared or isolated by methods known in the art.

The (SR)-substituted aminoalcohol (I) is an amine and as such form saltswhen reacted with acids. Pharmaceutically acceptable salts are preferredover the cor-responding substituted aminoalcoholds (I) since theyproduce compounds which are more water soluble, stable and/or morecrystalline. Pharmaceutically acceptable salts are any salt whichretains the activity of the parent compound and does not impart anydeleterious or undesirable effect on the subject to whom it isadministered and in the context in which it is administered.Pharmaceutically acceptable salts include salts of both inorganic andorganic acids. The preferred pharmaceutically acceptable salts includesalts of the following acids acetic, aspartic, benzenesulfonic, benzoic,bicarbonic, bisulfuric, bitartaric, butyric, calcium edetate, camsylic,carbonic, chlorobenzoic, citric, edetic, edisylic, estolic, esyl,esylic, formic, fumaric, gluceptic, gluconic, glutamic,glycollylarsanilic, hexamic, hexylresorcinoic, hydrabamic, hydrobromic,hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic,lactobionic, maleic, malic, malonic, mandelic, methanesulfonic,methylnitric, methylsulfuric, mucic, muconic, napsylic, nitric, oxalic,p-nitromethanesulfonic, pamoic, pantothenic, phosphoric, monohydrogenphosphoric, dihydrogen phosphoric, phthalic, polygalactouronic,propionic, salicylic, stearic, succinic, succinic, sulfamic, sulfanilic,sulfonic, sulfuric, tannic, tartaric, teoclic and toluenesulfonic. Forother acceptable salts, see Int. J. Pharm., 33, 201-217 (1986) andJ.Pharm.Sci., 66(1), 1, (1977).

The compounds of formula (I), and key portions thereof, such as theC-terminus of the compounds, may be prepared by the syntheticdescriptions of U.S. Pat. Nos. 5,606,078 and 5,559,111, both to Goschke,et. al.; U.S. Pat. No. 5,719,141, to Rasetti, et. al.; and U.S. Pat. No.5,641,778, to Maibaum, et. al., all incorporated herein by reference.

Synthetic Schemes AA-EE below further illustrate how to make substitutedamino acids which are useful in parparing the compounds of Formula (I).

As set forth in SCHEME AA, alcohol A, a protected form of serine, isconverted to halide B by the methods, for example, of Bajgrowicz et al.,Tetrahedron Letters, 2759 (1984) and Bajgrowicz et al., TetrahedronLetters, 1833 (1985), or by treatment of alcohol A with thionyl bromideor thionyl chloride in the presence of a catalytic amount of DMF and innon-reactive solvents such as THF, dichloromethane, and cyclohexane.Other methods for the conversion of alcohol A to halide B includecontact with carbon tetrabromide and triphenylphosphine in anon-reactive solvent such as dichloromethane. Other halogenatingreagents include, but are not limited to, trimethylsilylchloride,trimethylsilylbromide, and trimethylsilyliodide, and tosyl chloridefollowed by NaI. Halide B then may be allowed to react with variousamines, alcohols, and thiols in the presence of bases such as, but notlimited to, alkaline earth metal carbonates, alkali metal hydrides(preferably sodium or potassium hydride), alkaline earth metal hydrides,alkali metal dialkylamides (preferably litium diisopropylamide), alkalimetal bis(trialkylsilyl)amides, trialkyl amines (preferablytriethylamine and diisopropylethylamine) or aromatic amines (preferablypyridine), in non-reactive solvents such as acetonitrile, THF, DMF,dichloromethane and the like to give amide D.

In SCHEME AA, PG is PROTECTING GROUP as described above; A and W are asdescribed above; R₁ is C₁-C₄ alkyl or benzyl; halo is Cl, Br, or I. Inplace of halo can be any suitable leaving group, such as, —O-tosylate,—O-mesylate, or —O-triflate.

Treatment of halide B with base in non-reactive solvents such as THF oracetonitrile gives acrylate C. Acrylate C may be prepared directly fromalcohol A by converting the alcohol to a leaving group with reagentssuch as haloacetyl chlorides, mesyl chlorides, oxalyl chloride, diethylchloridophosphate, N-phenylditriflamide, and CDI, DCC, and the like inthe presence of a copper halide, followed by a base such as, but notlimited to, alkaline earth metal carbonates, alkali metal hydroxides,alkali metal hydrides (preferably sodium or potassium hydride), alkalimetal alkoxides (preferably sodium methoxide or sodium ethoxide),alkaline earth metal hydrides, alkali metal dialkylamides (preferablylitium diisopropylamide), alkali metal bis(trialkylsilyl)amides,trialkyl amines (preferably triethylamine and diisopropylethylamine) oraromatic amines (preferably pyridine).

Alternatively, alcohol A may be treated under Mitsunobu conditions withdialkyl azodicarboxylate, preferably diethyl diazodicarboxylate andtriphenyl phosphine in solvents such as THF to give cyclic amine B*,which is then treated in situ with amines, alcohols, and thiols in thepresence of bases such as, but not limited to, alkaline earth metalcarbonates, alkali metal hydroxides, alkali metal hydrides (preferablysodium or potassium hydride), alkaline earth metal hydrides, alkalimetal dialkylamides (preferably litium diisopropylamide), alkali metalbis(trialkylsilyl)amides, trialkyl amines (preferably triethylamine anddiisopropylethylamine) or aromatic amines (preferably pyridine) giveamide D.

Acrylate C is also an item of commerce. It is well known to those versedin the art how to add or remove or exchange one protecting group foranother as may be necessary depending upon the particular reactionintended. Treatment of acrylate C or halide B with amines, alcohols, andthiols in the presence of bases such as, but not limited to, alkalineearth metal carbonates, alkali metal hydroxides, alkali metal hydrides(preferably sodium or potassium hydride), alkaline earth metal hydrides,alkali metal dialkylamides (preferably lithium diisopropylamide), alkalimetal bis(trialkylsilyl)amides, trialkyl amines (preferablytriethylamine and diisopropylethylamine) or aromatic amines (preferablypyridine) in solvents such as THF or DMF at temperatures ranging fromroom temperature to reflux temperature of the solvent give amide D.

Amide D is hydrolyzed, preferably using alkali metal hydroxide such aslithium hydroxide, sodium hydroxide, or potassium hydroxide, followed byacidification, to give acid D-1, compounds of formula (II).

As set forth in SCHEME BB, the treatment of amide D withbromoiodobenzene (E) under conditions of the Heck reaction by meanswell-known to those versed in the art such as a palladium catalyst(preferably palladium acetate), an alkyl ammonium halide such astetra-n-butylammonium chloride, aq. base (preferably sodium bicarbonateor sodium carbonate), and solvents such as DMF, N-methylpyrrolidinone,N-methylacetamide, and the like at temperatures ranging from roomtemperature to the boiling point of the solvent, to give styrene F.Styrene F is further treated with alkene G under conditions of the Heckreaction by means well-known to those versed in the art. One suchexample of Heck reaction conditions are a palladium catalyst (preferablypalladium acetate), an alkyl ammonium halide such astetra-n-butylammonium chloride, aq. base (preferably sodium bicarbonateor sodium carbonate), and solvents such as DMF, N-methylpyrrolidinone,N-methylacetamide, and the like at temperatures ranging from roomtemperature to the boiling point of the solvent, to give dialkene H.Dialkene H is then reduced with hydrogen to alkane I using variouscatalysts and chiral ligands well known to those versed in the art togive the desired protected (S) amino acid I. One such catalyst andligand is (but is not limited to) Rh(COD)[(S,S)-Et-DuPHOS]⁺OTf. InSCHEME BB, PG is PROTECTING GROUP as described above; G is as describedabove; R₁ is C₁-C₄ alkyl or benzyl.

Protected amino acid (I) is hydrolyzed, preferably using alkali metalhydroxide such as lithium hydroxide, sodium hydroxide, or potassiumhydroxide, followed by acidification, to give acid I-1, compounds offormula (II).

As set forth in SCHEME CC, Aryl halide J, which is available as an itemof commerce, is reacted with borane reagents under conditions of theSuzuki reaction by methods well known to those versed in the art. InSCHEME CC, PG is PROTECTING GROUP as described above; G is as describedabove; R₁ is C₁-C₄ alkyl or benzyl.

Thus aryl halide J is treated with borane reagents K, L, and M where R′and R″ are, for example, OH, or OR where R is a lower alkyl, or where R′and R″ are C₁-C₈ alkyl or when taken together are C₈ cycloalkyl, in thepresence of a metal catalyst such as the salts or phosphine complexes ofCu, Pd, and Ni. Preferred are palladium catalysts such as PdCl₂(PPh₃)₂,PdCl₂(dppf), and Pd(OAc)₂ with or without added base, in solvents suchas THF, acetone, acetonitrile, dialkyl ethers, DMT, NMP,N,N-dialkylacetamides, and so forth, from about 50 degrees C. to refluxtemperature, to afford biphenyl N, benzylphenyl O, and alkyl phenyl P. Awide range of organoborane reagents can be made for use in thisderivatization by the hydroboration of alkenes with 9-BBN (J. Am. Chem.Soc., 314 (1989)), or by the methods described in Tetrahedron, 50, 979(1994).

Biphenyl N, benzylphenyl O, and alkyl phenyl P are hydrolyzed,preferably using alkali metal hydroxide such as lithium hydroxide,sodium hydroxide, or potassium hydroxide, followed by acidification, togive acids N-1, O-1, and P-1, compounds of formula (II).

As set forth in SCHEME DD, halobenzene S is prepared from commerciallyavailable benzene Q, a base, and alkyl halide G using methods well knownto those versed in the art. When G is desired to be aryl, then aryliodides are reacted with phenol Q or thiophenol Q using palladiumcatalysts as described in J. Am. Chem. Soc., 4369 (1999) and J. Am.Chem. Soc., 10539 (1997). Another method is combining thiophenol Q andaryl iodide R in the presence of a palladium catalyst such as Pd(PPh₃)₄and sodium tert-butoxide and ethanol give halobenzene S. When X isdesired to be nitrogen, aniline Q is reacted with iodobenzene R in thepresence of potassium or sodium tert-butoxide, Pd₂(dba)₃, BINAP, andtoluene to give halobenzene S. In SCHEME DD, PG is PROTECTING GROUP asdescribed above; G is as described above; R₁ is C₁-C₄ alkyl or benzyl.

The Heck reaction for the addition of halobenzene S to amide D to givealkene T is as described in SCHEME BB. Reduction of alkene T asdescribed in SCHEME BB gives amine U. When X is sulfur, it may bedesired to oxidize the sulfur to sulfone using m-chloroperoxybenzoicacid or hydrogen peroxide or other oxidizing agents, using methods wellknown to those versed in the art, to give sulfone V.

Amine U and sulfone V are hydrolyzed, preferably using alkali metalhydroxide such as lithium hydroxide, sodium hydroxide, or potassiumhydroxide, followed by acidification, to give acids U-1 and V-1,compounds of the formula (II).

SCHEME EE, Scheme E sets forth a route for the preparation ofbenzophenone AA and benzyl alcohol BB. In SCHEME EE, PG is PROTECTINGGROUP as described above; G is as described above; R₁ is C₁-C₄ alkyl orbenzyl.

Acetophenone Y is prepared from acid halide W (which, if notcommercially available, is prepared by numerous methods well known tothose skilled in the art, using commercially available benzoic acids).Acid halide W is reacted with a Grignard reagent (which is commerciallyavailable or prepared from available alkyl and aryl halides by methodswell known to those versed in the art) in solvents such as THF and attemperatures ranging from −78 degrees C. to room temperature to produceacetophenone Y. Alternatively, contacting HN(Me)(OMe) with acid halide Win neutral solvents such as THF, acetonitrile, or dichloromethane in thepresence of a base gives Weinreb amide X, which upon addition of aGrignard reagent in solvents such as THF at temperatures ranging from−78 degrees C. to room temperature to give acetophone Y. Acetophenone Yand amide D are then reacted under the conditions of the Heck reactiondiscussed in SCHEME BB to give alkene Z. Alkene Z is reduced to ketoneAA and benzyl alcohol BB using H₂ and metal catalysts such as palladiumon carbon in solvents such as alcohols, preferably C₁-C₄ alcohols, orRuCl₂ in the presence of a phosphine ligand and potassium tert-butoxidein solvents such as isopropanol, or using conditions of the Heckreaction as described in SCHEME BB. Benzyl alcohol BB may be oxidizedusing oxidizing agents well known to those versed in the art, forexample with activated manganese dioxide in non-reactive solvents suchas chloroform to give ketone AA. Alternatively, ketone AA may beproduced by reacting aryl halide J with a palladium catalyst, preferablyPdCl₂(PPh₃)₂, carbon monoxide, Ph(n-butyl)₃Sn, and DMF according to themethod of Bioorg. Med. Chem. Lett., 10, 1815 (2000). Ketone AA andalcohol BB are hydrolyzed, preferably using alkali metal hydroxide suchas lithium hydroxide, sodium hydroxide, or potassium hydroxide, followedby acidification, to give acids AA-1 and BB-1, compounds of the formula(II).

Synthesis of Boc-3,5-difluorophenylalanine threo epoxide startingmaterial was adapted from the procedure of Luly, JR, et al. J. Org.Chem. 1987, 52, 1487-1492 for the synthesis of Boc-phenylalanine threoepoxide (Scheme II). The starting material utilized in the preparationof Boc-3,5-difluorophenylalanine threo epoxide was Boc protectedl-3,5-difluorophenylalanine available from Synthetech, Inc. (1290Industrial Way, P. O. Box 646, Albany, Oreg. 97321 USA). TetrahedronLett., 38, 3175 (1997) further discloses a process for the preparationof N-BOC protected epoxides from protected amino acid esters.

The invention provides compounds, compositions, kits, and methods forinhibiting beta-secretase enzyme activity and A beta peptide production.Inhibition of beta-secretase enzyme activity halts or reduces theproduction of A beta from APP and reduces or eliminates the formation ofbeta-amyloid deposits in the brain.

METHODS OF THE INVENTION

The compounds of the invention, and pharmaceutically acceptable saltsthereof, are useful for treating humans or animals suffering from acondition characterized by a pathological form of beta-amyloid peptide,such as beta-amyloid plaques, and for helping to prevent or delay theonset of such a condition. For example, the compounds are useful fortreating Alzheimer's disease, for helping prevent or delay the onset ofAlzheimer's disease, for treating patients with MCI (mild cognitiveimpairment) and preventing or delaying the onset of Alzheimer's diseasein those who would progress from MCI to AD, for treating Down'ssyndrome, for treating humans who have Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch-Type, for treating cerebral amyloidangiopathy and preventing its potential consequences, i.e. single andrecurrent lobal hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, dementiaassociated with Parkinson's disease, dementia associated withprogressive supranuclear palsy, dementia associated with cortical basaldegeneration, and diffuse Lewy body type Alzheimer's disease. Thecompounds and compositions of the invention are particularly useful fortreating or preventing Alzheimer's disease. When treating or preventingthese diseases, the compounds of the invention can either be usedindividually or in combination, as is best for the patient.

As used herein, the term “treating” means that the compounds of theinvention can be used in humans with at least a tentative diagnosis ofdisease. The compounds of the invention will delay or slow theprogression of the disease thereby giving the individual a more usefullife span.

The term “preventing” means that the compounds of the invention areuseful when administered to a patient who has not been diagnosed aspossibly having the disease at the time of administration, but who wouldnormally be expected to develop the disease or be at increased risk forthe disease. The compounds of the invention will slow the development ofdisease symptoms, delay the onset of the disease, or prevent theindividual from developing the disease at all. Preventing also includesadministration of the compounds of the invention to those individualsthought to be predisposed to the disease due to age, familial history,genetic or chromosomal abnormalities, and/or due to the presence of oneor more biological markers for the disease, such as a known geneticmutation of APP or APP cleavage products in brain tissues or fluids.

In treating or preventing the above diseases, the compounds of theinvention are administered in a therapeutically effective amount. Thetherapeutically effective amount will vary depending on the particularcompound used and the route of administration, as is known to thoseskilled in the art.

In treating a patient displaying any of the diagnosed above conditions aphysician may administer a compound of the invention immediately andcontinue administration indefinitely, as needed. In treating patientswho are not diagnosed as having Alzheimer's disease, but who arebelieved to be at substantial risk for Alzheimer's disease, thephysician should preferably start treatment when the patient firstexperiences early pre-Alzheimer's symptoms such as, memory or cognitiveproblems associated with aging. In addition, there are some patients whomay be determined to be at risk for developing Alzheimer's through thedetection of a genetic marker such as APOE4 or other biologicalindicators that are predictive for Alzheimer's disease. In thesesituations, even though the patient does not have symptoms of thedisease, administration of the compounds of the invention may be startedbefore symptoms appear, and treatment may be continued indefinitely toprevent or delay the outset of the disease.

Dosage Forms and Amounts

The compounds of the invention can be administered orally,parenternally, (IV, IM, depo-IM, SQ, and depo SQ), sublingually,intranasally (inhalation), intrathecally, topically, or rectally. Dosageforms known to those of skill in the art are suitable for delivery ofthe compounds of the invention.

Compositions are provided that contain therapeutically effective amountsof the compounds of the invention. The compounds are preferablyformulated into suitable pharmaceutical preparations such as tablets,capsules, or elixirs for oral administration or in sterile solutions orsuspensions for parenternal administration. Typically the compoundsdescribed above are formulated into pharmaceutical compositions usingtechniques and procedures well known in the art.

About 1 to 500 mg of a compound or mixture of compounds of the inventionor a physiologically acceptable salt or ester is compounded with aphysiologically acceptable vehicle, carrier, excipient, binder,preservative, stabilizer, flavor, etc., in a unit dosage form as calledfor by accepted pharmaceutical practice. The amount of active substancein those compositions or preparations is such that a suitable dosage inthe range indicated is obtained. The compositions are preferablyformulated in a unit dosage form, each dosage containing from about 2 toabout 100 mg, more preferably about 10 to about 30 mg of the activeingredient. The term “unit dosage from” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

To prepare compositions, one or more compounds of the invention aremixed with a suitable pharmaceutically acceptable carrier. Upon mixingor addition of the compound(s), the resulting mixture may be a solution,suspension, emulsion, or the like. Liposomal suspensions may also besuitable as pharmaceutically acceptable carriers. These may be preparedaccording to methods known to those skilled in the art. The form of theresulting mixture depends upon a number of factors, including theintended mode of administration and the solubility of the compound inthe selected carrier or vehicle. The effective concentration issufficient for lessening or ameliorating at least one symptom of thedisease, disorder, or condition treated and may be empiricallydetermined.

Pharmaceutical carriers or vehicles suitable for administration of thecompounds provided herein include any such carriers known to thoseskilled in the art to be suitable for the particular mode ofadministration. In addition, the active materials can also be mixed withother active materials that do not impair the desired action, or withmaterials that supplement the desired action, or have another action.The compounds may be formulated as the sole pharmaceutically activeingredient in the composition or may be combined with other activeingredients.

Where the compounds exhibit insufficient solubility, methods forsolubilizing may be used. Such methods are known and include, but arenot limited to, using cosolvents such as dimethylsulfoxide DMSO), usingsurfactants such as Tween®, and dissolution in aqueous sodiumbicarbonate. Derivatives of the compounds, such as salts or prodrugs mayalso be used in formulating effective pharmaceutical compositions.

The concentration of the compound is effective for delivery of an amountupon administration that lessens or ameliorates at least one symptom ofthe disorder for which the compound is administered. Typically, thecompositions are formulated for single dosage administration.

The compounds of the invention may be prepared with carriers thatprotect them against rapid elimination from the body, such astime-release formulations or coatings. Such carriers include controlledrelease formulations, such as, but not limited to, microencapsulateddelivery systems. The active compound is included in thepharmaceutically acceptable carrier in an amount sufficient to exert atherapeutically useful effect in the absence of undesirable side effectson the patient treated. The therapeutically effective concentration maybe determined empirically by testing the compounds in known in vitro andin vivo model systems for the treated disorder.

The compounds and compositions of the invention can be enclosed inmultiple or single dose containers. The enclosed compounds andcompositions can be provided in kits, for example, including componentparts that can be assembled for use. For example, a compound inhibitorin lyophilized form and a suitable diluent may be provided as separatedcomponents for combination prior to use. A kit may include a compoundinhibitor and a second therapeutic agent for co-administration. Theinhibitor and second therapeutic agent may be provided as separatecomponent parts. A kit may include a plurality of containers, eachcontainer holding one or more unit dose of the compound of theinvention. The containers are preferably adapted for the desired mode ofadministration, including, but not limited to tablets, gel capsules,sustained-release capsules, and the like for oral administration; depotproducts, pre-filled syringes, ampules, vials, and the like forparenternal administration; and patches, medipads, creams, and the likefor topical administration.

The concentration of active compound in the drug composition will dependon absorption, inactivation, and excretion rates of the active compound,the dosage schedule, and amount administered as well as other factorsknown to those of skill in the art.

The active ingredient may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage valuesmay also vary with the severity of the condition to be alleviated. It isto be further understood that for any particular subject, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions, and that theconcentration ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed compositions.

If oral administration is desired, the compound should be provided in acomposition that protects it from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coatingthat maintains its integrity in the stomach and releases the activecompound in the intestine. The composition may also be formulated incombination with an antacid or other such ingredient.

Oral compositions will generally include an inert diluent or an ediblecarrier and may be compressed into tablets or enclosed in gelatincapsules. For the purpose of oral therapeutic administration, the activecompound or compounds can be incorporated with excipients and used inthe form of tablets, capsules, or troches. Pharmaceutically compatiblebinding agents and adjuvant materials can be included as part of thecomposition.

The tablets, pills, capsules, troches, and the like can contain any ofthe following ingredients or compounds of a similar nature: a bindersuch as, but not limited to, gum tragacanth, acacia, corn starch, orgelatin; an excipient such as microcrystalline cellulose, starch, orlactose; a disintegrating agent such as, but not limited to, alginicacid and corn starch; a lubricant such as, but not limited to, magnesiumstearate; a gildant, such as, but not limited to, colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; and aflavoring agent such as peppermint, methyl salicylate, or fruitflavoring.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials, whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, chewing gum orthe like. A syrup may contain, in addition to the active compounds,sucrose as a sweetening agent and certain preservatives, dyes andcolorings, and flavors.

The active materials can also be mixed with other active materials thatdo not impair the desired action, or with materials that supplement thedesired action.

Solutions or suspensions used for parenternal, intradermal,subcutaneous, or topical application can include any of the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oil, a naturally occurring vegetable oil such as sesameoil, coconut oil, peanut oil, cottonseed oil, and the like, or asynthetic fatty vehicle such as ethyl oleate, and the like, polyethyleneglycol, glycerine, propylene glycol, or other synthetic solvent;antimicrobial agents such as benzyl alcohol and methyl parabens;antioxidants such as ascorbic acid and sodium bisulfite; chelatingagents such as ethylenediaminetetraacetic acid (EDTA); buffers such asacetates, citrates, and phosphates; and agents for the adjustment oftonicity such as sodium chloride and dextrose. Parenternal preparationscan be enclosed in ampoules, disposable syringes, or multiple dose vialsmade of glass, plastic, or other suitable material. Buffers,preservatives, antioxidants, and the like can be incorporated asrequired.

Where administered intravenously, suitable carriers includephysiological saline, phosphate buffered saline (PBS), and solutionscontaining thickening and solubilizing agents such as glucose,polyethylene glycol, polypropyleneglycol, and mixtures thereof Liposomalsuspensions including tissue-targeted liposomes may also be suitable aspharmaceutically acceptable carriers. These may be prepared according tomethods known for example, as described in U.S. Pat. No. 4,522,811.

The active compounds may be prepared with carriers that protect thecompound against rapid elimination from the body, such as time-releaseformulations or coatings. Such carriers include controlled releaseformulations, such as, but not limited to, implants andmicroencapsulated delivery systems, and biodegradable, biocompatiblepolymers such as collagen, ethylene vinyl acetate, polyanhydrides,polyglycolic acid, polyorthoesters, polylactic acid, and the like.Methods for preparation of such formulations are known to those skilledin the art.

The compounds of the invention can be administered orally, parenternally(IV, IM, depo-IM, SQ, and depo-SQ), sublingually, intranasally(inhalation), intrathecally, topically, or rectally. Dosage forms knownto those skilled in the art are suitable for delivery of the compoundsof the invention.

Compounds of the invention may be administered enterally orparenterally. When administered orally, compounds of the invention canbe administered in usual dosage forms for oral administration as is wellknown to those skilled in the art. These dosage forms include the usualsolid unit dosage forms of tablets and capsules as well as liquid dosageforms such as solutions, suspensions, and elixirs. When the solid dosageforms are used, it is preferred that they be of the sustained releasetype so that the compounds of the invention need to be administered onlyonce or twice daily. The oral dosage forms are administered to thepatient 1, 2, 3, or 4 times daily. It is preferred that the compounds ofthe invention be administered either three or fewer times, morepreferably once or twice daily. Hence, it is preferred that thecompounds of the invention be administered in oral dosage form. It ispreferred that whatever oral dosage form is used, that it be designed soas to protect the compounds of the invention from the acidic environmentof the stomach. Enteric coated tablets are well known to those skilledin the art. In addition, capsules filled with small spheres each coatedto protect from the acidic stomach, are also well known to those skilledin the art.

When administered orally, an administered amount therapeuticallyeffective to inhibit beta-secretase activity, to inhibit A betaproduction, to inhibit A beta deposition, or to treat or prevent AD isfrom about 0.1 mg/day to about 1,000 mg/day. It is preferred that theoral dosage is from about 1 mg/day to about 100 mg/day. It is morepreferred that the oral dosage is from about 5 mg/day to about 50mg/day. It is understood that while a patient may be started at onedose, that dose may be varied over time as the patient's conditionchanges.

Compounds of the invention may also be advantageously delivered in anano crystal dispersion formulation. Preparation of such formulations isdescribed, for example, in U.S. Pat. No. 5,145,684. Nano crystallinedispersions of HIV protease inhibitors and their method of use aredescribed in U.S. Pat. No. 6,045,829. The nano crystalline formulationstypically afford greater bioavailability of drug compounds.

The compounds of the invention can be administered parenterally, forexample, by IV, IM, depo-IM, SC, or depo-SC. When administeredparenterally, a therapeutically effective amount of about 0.5 to about100 mg/day, preferably from about 5 to about 50 mg daily should bedelivered. When a depot formulation is used for injection once a monthor once every two weeks, the dose should be about 0.5 mg/day to about 50mg/day, or a monthly dose of from about 15 mg to about 1,500 mg. In partbecause of the forgetfulness of the patients with Alzheimer's disease,it is preferred that the parenteral dosage form be a depo formulation.

The compounds of the invention can be administered sublingually. Whengiven sublingually, the compounds of the invention should be given oneto four times daily in the amounts described above for IN administration

The compounds of the invention can be administered intranasally. Whengiven by this route, the appropriate dosage forms are a nasal spray ordry powder, as is known to those skilled in the art. The dosage of thecompounds of the invention for intranasal administration is the amountdescribed above for IM administration.

The compounds of the invention can be administered intrathecally. Whengiven by this route the appropriate dosage form can be a parenternaldosage form as is known to those skilled in the art. The dosage of thecompounds of the invention for intrathecal administration is the amountdescribed above for IM administration.

The compounds of the invention can be administered topically. When givenby this route, the appropriate dosage form is a cream, ointment, orpatch. Because of the amount of the compounds of the invention to beadministered, the patch is preferred. When administered topically, thedosage is from about 0.5 mg/day to about 200 mg/day. Because the amountthat can be delivered by a patch is limited, two or more patches may beused. The number and size of the patch is not important, what isimportant is that a therapeutically effective amount of the compounds ofthe invention be delivered as is known to those skilled in the art. Thecompounds of the invention can be administered rectally by suppositoryas is known to those skilled in the art. When administered bysuppository, the therapeutically effective amount is from about 0.5 mgto about 500 mg.

The compounds of the invention can be administered by implants as isknown to those skilled in the art. When administering a compound of theinvention by implant, the therapeutically effective amount is the amountdescribed above for depot administration.

The invention here is the new compounds of the invention and new methodsof using the compounds of the invention. Given a particular compound ofthe invention and a desired dosage form, one skilled in the art wouldknow how to prepare and administer the appropriate dosage form.

The compounds of the invention are used in the same manner, by the sameroutes of administration, using the same pharmaceutical dosage forms,and at the same dosing schedule as described above, for preventingdisease or treating patients with MCI (mild cognitive impairment) andpreventing or delaying the onset of Alzheimer's disease in those whowould progress from MCI to AD, for treating or preventing Down'ssyndrome, for treating humans who have Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch-Type, for treating cerebral amyloidangiopathy and preventing its potential consequences, i.e. single andrecurrent lobar hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, dementiaassociated with Parkinson's disease, dementia associated withprogressive supranuclear palsy, dementia associated with cortical basaldegeneration, and diffuse Lewy body type of Alzheimer's disease.

The compounds of the invention can be used in combination, with eachother or with other therapeutic agents or approaches used to treat orprevent the conditions listed above. Such agents or approaches include:acetylcholine esterase inhibitors such as tacrine(tetrahydroaminoacridine, marketed as COGNEX®), donepezil hydrochloride,(marketed as Aricept® and rivastigmine (marketed as Exelon®);gamma-secretase inhibitors; anti-inflammatory agents such ascyclooxygenase II inhibitors; anti-oxidants such as Vitamin E andginkolides; immunological approaches, such as, for example, immunizationwith A beta peptide or administration of anti-A beta peptide antibodies;statins; and direct or indirect neurotropic agents such asCerebrolysin®, AIT-082 (Emilieu, 2000, Arch. Neurol 57:454), and otherneurotropic agents of the future.

It should be apparent to one skilled in the art that the exact dosageand frequency of administration will depend on the particular compoundsof the invention administered, the particular condition being treated,the severity of the condition being treated, the age, weight, generalphysical condition of the particular patient, and other medication theindividual may be taking as is well known to administering physicianswho are skilled in this art.

Inhibition of APP Cleavage

The compounds of the invention inhibit cleavage of APP between Met595and Asp596 numbered for the APP695 isoform, or a mutant thereof, or at acorresponding site of a different isoform, such as APP751 or APP770, ora mutant thereof (sometimes referred to as the “beta secretase site”).While not wishing to be bound by a particular theory, inhibition ofbeta-secretase activity is thought to inhibit production of beta amyloidpeptide (A beta). inhibitory activity is demonstrated in one of avariety of inhibition assays, whereby cleavage of an APP substrate inthe presence of a beta-secretase enzyme is analyzed in the presence ofthe inhibitory compound, under conditions normally sufficient to resultin cleavage at the beta-secretase cleavage site. Reduction of APPcleavage at the beta-secretase cleavage site compared with an untreatedor inactive control is correlated with inhibitory activity. Assaysystems that can be used to demonstrate efficacy of the compoundinhibitors of the invention are known. Representative assay systems aredescribed, for example, in U.S. Pat. Nos. 5,942,400, 5,744,346, as wellas in the Examples below.

The enzymatic activity of beta-secretase and the production of A betacan be analyzed in vitro or in vivo, using natural, mutated, and/orsynthetic APP substrates, natural, mutated, and/or synthetic enzyme, andthe test compound. The analysis may involve primary or secondary cellsexpressing native, mutant, and/or synthetic APP and enzyme, animalmodels expressing native APP and enzyme, or may utilize transgenicanimal models expressing the substrate and enzyme. Detection ofenzymatic activity can be by analysis of one or more of the cleavageproducts, for example, by immunoassay, flurometric or chromogenic assay,HPLC, or other means of detection. Inhibitory compounds are determinedas those having the ability to decrease the amount of beta-secretasecleavage product produced in comparison to a control, wherebeta-secretase mediated cleavage in the reaction system is observed andmeasured in the absence of inhibitory compounds.

Beta-Secretase

Various forms of beta-secretase enzyme are known, and are available anduseful for assay of enzyme activity and inhibition of enzyme activity.These include native, recombinant, and synthetic forms of the enzyme.Human beta-secretase is known as Beta Site APP Cleaving Enzyme (BACE),Asp2, and memapsin 2, and has been characterized, for example, in U.S.Pat. No. 5,744,346 and published PCT patent applications WO98/22597,WO00/03819, WO01/23533, and WO00/17369, as well as in literaturepublications (Hussain et.al., 1999, Mol.Cell.Neurosci. 14:419-427;Vassar et.al., 1999, Science 286:735-741; Yan et.al., 1999, Nature402:533-537; Sinha et.al., 1999, Nature 40:537-540; and Lin et.al.,2000, PNAS USA 97:1456-1460). Synthetic forms of the enzyme have alsobeen described (WO98/22597 and WO00/17369). Beta-secretase can beextracted and purified from human brain tissue and can be produced incells, for example mammalian cells expressing recombinant enzyme.

Preferred compounds are effective to inhibit 50% of beta-secretaseenzymatic activity at a concentration of less than about 50 micromolar,preferably at a concentration of less than about 10 micromolar, morepreferably less than about 1 micromolar, and most preferably less thanabout 10 nanomolar.

APP Substrate

Assays that demonstrate inhibition of beta-secretase-mediated cleavageof APP can utilize any of the known forms of APP, including the 695amino acid “normal” isotype described by Kang et.al., 1987, Nature325:7336, the 770 amino acid isotype described by Kitaguchi et. al.,1981, Nature 331:530-532, and variants such as the Swedish Mutation(KM670-1NL) (APP-SW), the London Mutation (V7176F), and others. See, forexample, U.S. Pat. No. 5,766,846 and also Hardy, 1992, Nature Genet.1:233-234, for a review of known variant mutations. Additional usefulsubstrates include the dibasic amino acid modification, APP-KKdisclosed, for example, in WO 00/17369, fragments of APP, and syntheticpeptides containing the beta-secretase cleavage site, wild type (WT) ormutated form, e.g., SW, as described, for example, in U.S. Pat. No5,942,400 and WO00/03819.

The APP substrate contains the beta-secretase cleavage site of APP(KM-DA or NL-DA) for example, a complete APP peptide or variant, an APPfragment, a recombinant or synthetic APP, or a fusion peptide.Preferably, the fusion peptide includes the beta-secretase cleavage sitefused to a peptide having a moiety useful for enzymatic assay, forexample, having isolation and/or detection properties. A useful moietymay be an antigenic epitope for antibody binding, a label or otherdetection moiety, a binding substrate, and the like.

Antibodies

Products characteristic of APP cleavage can be measured by immunoassayusing various antibodies, as described, for example, in Pirttila et.al.,1999, Neuro.Lett. 249:21-4, and in U.S. Pat. No. 5,612,486. Usefulantibodies to detect A beta include, for example, the monoclonalantibody 6E10 (Senetek, St. Louis, Mo.) that specifically recognizes anepitope on amino acids 1-16 of the A beta peptide; antibodies 162 and164 (New York State Institute for Basic Research, Staten Island, N.Y.)that are specific for human A beta 1-40 and 1-42, respectively; andantibodies that recognize the junction region of beta-amyloid peptide,the site between residues 16 and 17, as described in U.S. Pat. No.5,593,846. Antibodies raised against a synthetic peptide of residues 591to 596 of APP and SW192 antibody raised against 590-596 of the Swedishmutation are also useful in immunoassay of APP and its cleavageproducts, as described in U.S. Pat. Nos. 5,604,102 and 5,721,130.

Assay Systems

Assays for determining APP cleavage at the beta-secretase cleavage siteare well known in the art. Exemplary assays, are described, for example,in U.S. Pat. Nos. 5,744,346 and 5,942,400, and described in the Examplesbelow.

Cell Free Assays

Exemplary assays that can be used to demonstrate the inhibitory activityof the compounds of the invention are described, for example, inWO00/17369, WO 00/03819, and U.S. Pat. No. 5,942,400 and 5,744,346. Suchassays can be performed in cell-free incubations or in cellularincubations using cells expressing a beta-secretase and an APP substratehaving a beta-secretase cleavage site.

An APP substrate containing the beat-secretase cleavage site of APP, forexample, a complete APP or variant, an APP fragment, or a recombinant orsynthetic APP substrate containing the amino acid sequence: KM-DA orNL-DA, is incubated in the presence of beta-secretase enzyme, a fragmentthereof, or a synthetic or recombinant polypeptide variant havingbeta-secretase activity and effective to cleave the beta-secretasecleavage site of APP, under incubation conditions suitable for thecleavage activity of the enzyme. Suitable substrates optionally includederivatives that may be fusion proteins or peptides that contain thesubstrate peptide and a modification useful to facilitate thepurification or detection of the peptide or its beta-secretase cleavageproducts. Useful modifications include the insertion of a knownantigenic epitope for antibody binding; the linking of a label ordetectable moiety, the linking of a binding substrate, and the like.

Suitable incubation conditions for a cell-free in vitro assay include,for example: approximately 200 nanomolar to 10 micromolar substrate,approximately 10 to 200 picomolar enzyme, and approximately 0.1nanomolar to 10 micromolar inhibitor compound, in aqueous solution, atan approximate pH of 4-7, at approximately 37 degrees C., for a timeperiod of approximately 10 minutes to 3 hours. These incubationconditions are exemplary only, and can be varied as required for theparticular assay components and/or desired measurement system.Optimization of the incubation conditions for the particular assaycomponents should account for the specific beta-secretase enzyme usedand its pH optimum, any additional enzymes and/or markers that might beused in the assay, and the like. Such optimization is routine and willnot require undue experimentation.

One useful assay utilizes a fusion peptide having maltose bindingprotein (MBP) fused to the C-terminal 125 amino acids of APP-SW. The MBPportion is captured on an assay substrate by anti-MBP capture antibody.Incubation of the captured fusion protein in the presence ofbeta-secretase results in cleavage of the substrate at thebeta-secretase cleavage site. Analysis of the cleavage activity can be,for example, by immunoassay of cleavage products. One such immunoassaydetects a unique epitope exposed at the carboxy terminus of the cleavedfusion protein, for example, using the antibody SW192. This assay isdescribed, for example, in U.S. Pat. No 5,942,400.

Cellular Assay

Numerous cell-based assays can be used to analyze beta-secretaseactivity and/or processing of APP to release A beta. Contact of an APPsubstrate with a beta-secretase enzyme within the cell and in thepresence or absence of a compound inhibitor of the invention can be usedto demonstrate beta-secretase inhibitory activity of the compound.Preferably, assay in the presence of a useful inhibitory compoundprovides at least about 30%, most preferably at least about 50%inhibition of the enzymatic activity, as compared with a non-inhibitedcontrol.

In one embodiment, cells that naturally express beta-secretase are used.Alternatively, cells are modified to express a recombinantbeta-secretase or synthetic variant enzyme as discussed above. The APPsubstrate may be added to the culture medium and is preferably expressedin the cells. Cells that naturally express APP, variant or mutant formsof APP, or cells transformed to express an isoform of APP, mutant orvariant APP, recombinant or synthetic APP, APP fragment, or syntheticAPP peptide or fusion protein containing the beta-secretase APP cleavagesite can be used, provided that the expressed APP is permitted tocontact the enzyme and enzymatic cleavage activity can be analyzed.

Human cell lines that normally process A beta from APP provide a usefulmeans to assay inhibitory activities of the compounds of the invention.Production and release of A beta and/or other cleavage products into theculture medium can be measured, for example by immunoassay, such asWestern blot or enzyme-linked immunoassay (EIA) such as by ELISA.

Cells expressing an APP substrate and an active beta-secretase can beincubated in the presence of a compound inhibitor to demonstrateinhibition of enzymatic activity as compared with a control. Activity ofbeta-secretase can be measured by analysis of one or more cleavageproducts of the APP substrate. For example, inhibition of beta-secretaseactivity against the substrate APP would be expected to decrease releaseof specific beta-secretase induced APP cleavage products such as A beta.

Although both neural and non-neural cells process and release A beta,levels of endogenous beta-secretase activity are low and often difficultto detect by EIA. The use of cell types known to have enhancedbeta-secretase activity, enhanced processing of APP to A beta, and/orenhanced production of A beta are therefore preferred For example,transfection of cells with the Swedish Mutant form of APP (APP-SW); withAPP-KK; or with APP-SW-KK provides cells having enhanced beta-secretaseactivity and producing amounts of A beta that can be readily measured.

In such assays, for example, the cells expressing APP and beta-secretaseare incubated in a culture medium under conditions suitable forbeta-secretase enzymatic activity at its cleavage site on the APPsubstrate. On exposure of the cells to the compound inhibitor, theamount of A beta released into the medium and/or the amount of CTF99fragments of APP in the cell lysates is reduced as compared with thecontrol. The cleavage products of APP can be analyzed, for example, byimmune reactions with specific antibodies, as discussed above.

Preferred cells for analysis of beta-secretase activity include primaryhuman neuronal cells, primary transgenic animal neuronal cells where thetransgene is APP, and other cells such as those of a stable 293 cellline expressing APP, for example, APP-SW.

In Vivo Assays: Animal Models

Various animal models can be used to analyze beta-secretase activityand/or processing of APP to release A beta, as described above. Forexample, transgenic animals expressing APP substrate and beta-secretaseenzyme can be used to demonstrate inhibitory activity of the compoundsof the invention. Certain transgenic animal models have been described,for example, in U.S. Pat. Nos: 5,877,399; 5,612,486; 5,387,742;5,720,936; 5,850,003; 5,877,015, and 5,811,633, and in Ganes et.al.,1995, Nature 373:523. Preferred are animals that exhibit characteristicsassociated with the pathophysiology of AD. Administration of thecompound inhibitors of the invention to the transgenic mice describedherein provides an alternative method for demonstrating the inhibitoryactivity of the compounds. Administration of the compounds in apharmaceutically effective carrier and via an administrative route thatreaches the target tissue in an appropriate therapeutic amount is alsopreferred.

Inhibition of beta-secretase mediated cleavage of APP at thebeta-secretase cleavage site and of A beta release can be analyzed inthese animals by measure of cleavage fragments in the animal's bodyfluids such as cerebral fluid or tissues. Analysis of brain tissues forA beta deposits or plaques is preferred.

On contacting an APP substrate with a beta-secretase enzyme in thepresence of an inhibitory compound of the invention and under conditionssufficient to permit enzymatic mediated cleavage of APP and/or releaseof A beta from the substrate, the compounds of the invention areeffective to reduce beta-secretase-mediated cleavage of APP at thebeta-secretase cleavage site and/or effective to reduce released amountsof A beta. Where such contacting is the administration of the inhibitorycompounds of the invention to an animal model, for example, as describedabove, the compounds are effective to reduce A beta deposition in braintissues of the animal, and to reduce the number and/or size of betaamyloid plaques. Where such administration is to a human subject, thecompounds are effective to inhibit or slow the progression of diseasecharacterized by enhanced amounts of A beta, to slow the progression ofAD in the, and/or to prevent onset or development of AD in a patient atrisk for the disease.

Unless defined otherwise, all scientific and technical terms used hereinhave the same meaning as commonly understood by one of skill in the artto which this invention belongs. All patents and publications referredto herein are hereby incorporated by reference for all purposes.

Definitions and Conventions

The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims.

Definitions

All temperatures are in degrees Celsius.

TLC refers to thin-layer chromatography.

psi refers to pounds/in².

HPLC refers to high pressure liquid chromatography.

THF refers to tetrahydrofuran.

DMF refers to dimethylformamide.

EDC refers to ethyl-1-(3-dimethylaminopropyl)carbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

HOBt refers to 1-hydroxy benzotriazole hydrate.

NMM refers to N-methylmorpholine.

NBS refers to N-bromosuccinmide.

TEA refers to triethylamine.

BOC refers to 1,1-dimethylethoxy carbonyl or t-butoxycarbonyl,represented schematically as —CO—O—C(CH₃)₃.

CBZ refers to benzyloxycarbonyl, —CO—O—CH₂-φ).

FMOC refers to 9-fluorenylmethyl carbonate.

TFA refers to trifluoracetic acid, CF₃—COOH.

CDI refers to 1,1′-carbonyldiimidazole.

Saline refers to an aqueous saturated sodium chloride solution.

Chromatography (column and flash chromatography) refers topurification/separation of compounds expressed as (support, eluent). Itis understood that the appropriate fractions are pooled and concentratedto give the desired compound(s).

CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts arereported in ppm (δ) downfield from TMS.

NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemicalshifts are reported in ppm (d) downfield from TMS.

IR refers to infrared spectroscopy.

-phenyl refers to phenyl (C₆H₅).

MS refers to mass spectrometry expressed as m/e, m/z or mass/chargeunit. MH³⁰ refers to the positive ion of a parent plus a hydrogen atom.EI refers to electron impact. CI refers to chemical ionization. FABrefers to fast atom bombardment.

HRMS refers to high resolution mass spectrometry.

Ether refers to diethyl ether.

Pharmaceutically acceptable refers to those properties and/or substanceswhich are acceptable to the patient from a pharmacological/toxicologicalpoint of view and to the manufacturing pharmaceutical chemist from aphysical/chemical point of view regarding composition, formulation,stability, patient acceptance and bioavailability.

When solvent pairs are used, the ratios of solvents used arevolume/volume (v/v).

When the solubility of a solid in a solvent is used the ratio of thesolid to the solvent is weight/volume (wt/v).

BOP refers to benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate.

TBDMSCl refers to t-butyldimethylsilyl chloride.

TBDMSOTf refers to t-butyldimethylsilyl trifluosulfonic acid ester.

Trisomy 21 refers to Down's Syndrome.

APP, amyloid precursor protein, is defined as any APP polypeptide,including APP variants, mutations, and isoforms, for example, asdisclosed in U.S. Pat. No. 5,766,846.

A beta, amyloid beta peptide, is defined as any peptide resulting frombeta-secretase mediated cleavage of APP, including peptides of 39, 40,41, 42, and 43 amino acids, and extending from the beta-secretasecleavage site to amino acids 39, 40, 41, 42, or 43.

Beta-secretase (BACE1, Asp2, Memapsin 2) is an aspartyl protease thatmediates cleavage of APP at the amino-terminal edge of A beta Humanbeta-secretase is described, for example, in WO00/17369.

“Pharmaceutically acceptable” refers to those properties and/orsubstances that are acceptable to the patient from apharmacological/toxicological point of view and to the manufacturingpharmaceutical chemist from a physical/chemical point of view regardingcomposition, formulation, stability, patient acceptance andbioavailability.

A therapeutically effective amount is defined as an amount effective toreduce or lessen at least one symptom of the disease being treated or toreduce or delay onset of one or more clinical markers or symptoms of thedisease.

BIOLOGY EXAMPLES Example A

Enzyme Inhibition Assay

The compounds of the invention are analyzed for inhibitory activity byuse of the MBP-C125 assay. This assay determines the relative inhibitionof beta-secretase cleavage of a model APP substrate, MBP-C125SW, by thecompounds assayed as compared with an untreated control. A detaileddescription of the assay parameters can be found, for example, in U.S.Pat. No. 5,942,400. Briefly, the substrate is a fusion peptide formed ofmaltose binding protein (MBP) and the carboxy terminal 125 amino acidsof APP-SW, the Swedish mutation. The beta-secretase enzyme is derivedfrom human brain tissue as described in Sinha et.al, 1999, Nature40:537-540) or recombinantly produced as the full-length enzyme (aminoacids 1-501), and can be prepared, for example, from 293 cellsexpressing the recombinant cDNA, as described in WO00/47618. Human brainβ-Secretase from concentrated HiQ pool prepared 7/16/97 in 0.20% Tritonwas used in the assay.

Inhibition of the enzyme is analyzed, for example, by immunoassay of theenzyme's cleavage products. One exemplary ELISA uses an anti-MBP captureantibody that is deposited on precoated and blocked 96-well high bindingplates, followed by incubation with diluted enzyme reaction supernatant,incubation with a specific reporter antibody, for example, biotinylatedanti-SW192 reporter antibody, and further incubation withstreptavidin/alkaline phosphatase. In the assay, cleavage of the intactMBP-C125SW fusion protein results in the generation of a truncatedamino-terminal fragment, exposing a new SW-192 antibody-positive epitopeat the carboxy terminus. Detection is effected by a fluorescentsubstrate signal on cleavage by the phosphatase. ELISA only detectscleavage following Leu 596 at the substrate's APP-SW 751 mutation site.Specific Assay Procedure:

Compounds are diluted in a 1:1 dilution series to a six-pointconcentration curve (two wells per concentration) in one 96-plate rowper compound tested. Each of the test compounds is prepared in DMSO tomake up a 10 millimolar stock solution. The stock solution is seriallydiluted in DMSO to obtain a final compound concentration of 200micromolar at the high point of a 6-point dilution curve. Ten (10)microliters of each dilution is added to each of two wells on row C of acorresponding V-bottom plate to which 190 microliters of 52 millimolarNaOAc, 7.9% DMSO, pH 4.5 are pre-added. The NaOAc diluted compound plateis spun down to pellet precipitant and 20 microliters/well istransferred to a corresponding flat-bottom plate to which 30 microlitersof ice-cold enzyme-substrate mixture (2.5 microliters MBP-C125SWsubstrate, 0.03 microliters enzyme and 24.5 microliters ice cold 0.09%TX100 per 30 microliters) is added. The final reaction mixture of 200micromolar compound at the highest curve point is in 5% DMSO, 20millimolar NaAc, 0.06% TX100, at pH 4.5.

Warming the plates to 37 degrees C. starts the enzyme reaction. After 90minutes at 37 degrees C., 200 microliters/well cold specimen diluent isadded to stop the reaction and 20 microliters/well was transferred to acorresponding anti-MBP antibody coated ELISA plate for capture,containing 80 microliters/well specimen diluent. This reaction isincubated overnight at 4 degrees C. and the ELISA is developed the nextday after a 2 hour incubation with anti-192SW antibody, followed byStreptavidin-AP conjugate and fluorescent substrate. The signal is readon a fluorescent plate reader.

Relative compound inhibition potency is determined by calculating theconcentration of compound that showed a fifty percent reduction indetected signal (IC₅₀) compared to the enzyme reaction signal in thecontrol wells with no added compound.

Example B

Cell Free Inhibition Assay Utilizing a Synthetic APP Substrate

A synthetic APP substrate that can be cleaved by beta-secretase andhaving N—terminal biotin and made fluorescent by the covalent attachmentof Oregon green at the Cys residue is used to assay beta-secretaseactivity in the presence or absence of the inhibitory compounds of theinvention. Useful substrates include the following:

[SEQ ID NO:1] Biotin-SEVNL-DAEFRC[Oregon green]KK [SEQ ID NO:2]Biotin-SEVKM-DAEFRC[Oregon green]KK [SEQ ID NO:3]Biotin-GLNIKTEEISEISY-EVEFRC[Oregon green]KK [SEQ ID NO:4]Biotin-ADRGLTTRPGSGLTNIKTEEISEVNL-DAEFC [Oregon green]KK [SEQ ID NO:5]Biotin-FVNQHLCoxGSHLVEALY- LVCoxGERGFFYTPKAC[Oregon green]KK

The enzyme (0.1 nanomolar) and test compounds (0.001-100 micromolar) areincubated in pre-blocked, low affinity, black plates (384 well) at 37degrees for 30 minutes. The reaction is initiated by addition of 150millimolar substrate to a final volume of 30 microliter per well. Thefinal assay conditions are: 0.001 -100 micromolar compound inhibitor;0.1 molar sodium acetate (pH 4.5); 150 nanomolar substrate; 0.1nanomolar soluble beta-secretase; 0.001% Tween 20, and 2% DMSO. Theassay mixture is incubated for 3 hours at 37 degrees C., and thereaction is terminated by the addition of a saturating concentration ofimmunopure streptavidin. After incubation with streptavidin at roomtemperature for 15 minutes, fluorescence polarization is measured, forexample, using a LJL Acqurest (Ex485 nm/Em530 nm). The activity of thebeta-secretase enzyme is detected by changes in the fluorescencepolarization that occur when the substrate is cleaved by the enzyme.Incubation in the presence or absence of compound inhibitor demonstratesspecific inhibition of beta-secretase enzymatic cleavage of itssynthetic APP substrate.

Example C

Beta-Secretase Inhibition: P26-P4′SW Assay

Synthetic substrates containing the beta-secretase cleavage site of APPare used to assay beta-secretase activity, using the methods described,for example, in published PCT application WO00/47618. The P26-P4′SWsubstrate is a peptide of the sequence:

[SEQ ID NO:6] (biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNLDAEF

The P26-P1 standard has the sequence:

[SEQ ID NO:7] (biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNL.

Briefly, the biotin-coupled synthetic substrates are incubated at aconcentration of from about 0 to about 200 micromolar in this assay.When testing inhibitory compounds, a substrate concentration of about1.0 micromolar is preferred. Test compounds diluted in DMSO are added tothe reaction mixture, with a final DMSO concentration of 5%. Controlsalso contain a final DMSO concentration of 5%. The concentration of betasecretase enzyme in the reaction is varied, to give productconcentrations with the linear range of the ELISA assay, about 125 to2000 picomolar, after dilution.

The reaction mixture also includes 20 millimolar sodium acetate, pH 4.5,0.06% Triton X 100, and is incubated at 37 degrees C. for about 1 to 3hours. Samples are then diluted in assay buffer (for example, 145.4nanomolar sodium chloride, 9.51 millimolar sodium phosphate, 7.7millimolar sodium azide, 0.05% Triton X405, 6g/liter bovine serumalbumin, pH 7.4) to quench the reaction, then diluted further forimmunoassay of the cleavage products.

Cleavage products can be assayed by ELISA. Diluted samples and standardsare incubated in assay plates coated with capture antibody, for example,SW192, for about 24 hours at 4 degrees C. After washing in TTBS buffer(150 millimolar sodium chloride, 25 millimolar Tris, 0.05% Tween 20, pH7.5), the samples are incubated with streptavidin-AP according to themanufacturer's instructions. After a one hour incubation at roomtemperature, the samples are washed in TTBS and incubated withfluorescent substrate solution A (31.2 g/liter2-amino-2-methyl-1-propanol, 30 mg/liter, pH 9.5). Reaction withstreptavidin-alkaline phosphate permits detection by fluorescence.Compounds that are effective inhibitors of beta-secretase activitydemonstrate reduced cleavage of the substrate as compared to a control.

Example D

Assays using Synthetic Oligopeptide-Substrates

Synthetic oligopeptides are prepared that incorporate the known cleavagesite of beta-secretase, and optionally detectable tags, such asfluorescent or chromogenic moieties. Examples of such peptides, as wellas their production and detection methods are described in U.S. Pat. No:5,942,400, herein incorporated by reference. Cleavage products can bedetected using high performance liquid chromatography, or fluorescent orchromogenic detection methods appropriate to the peptide to be detected,according to methods well known in the art.

By way of example, one such peptide has the sequence SEVNL-DAEF [SEQ IDNO: 8], and the cleavage site is between residues 5 and 6. Anotherpreferred substrate has the sequence ADRGLTTRPGSGLTNIKTEEISEVNL-DAEF[SEQ ID NO: 9], and the cleavage site is between residues 26 and 27.

These synthetic APP substrates are incubated in the presence ofbeta-secretase under conditions sufficient to result in beta-secretasemediated cleavage of the substrate. Comparison of the cleavage resultsin the presence of the compound inhibitor to control results provides ameasure of the compound's inhibitory activity.

Example E

Inhibition of Beta-Secretase Activity-Cellular Assay

An exemplary assay for the analysis of inhibition of beta-secretaseactivity utilizes the human embryonic kidney cell line HEKp293 (ATCCAccession No. CRL-1573) transfected with APP751 containing the naturallyoccurring double mutation Lys651Met52 to Asn651Leu652 (numbered forAPP751), commonly called the Swedish mutation and shown to overproduce Abeta (Citron et.al., 1992, Nature 360:672-674), as described in U.S.Pat. No. 5,604,102.

The cells are incubated in the presence/absence of the inhibitorycompound (diluted in DMSO) at the desired concentration, generally up to10 micrograms/ml. At the end of the treatment period, conditioned mediais analyzed for beta-secretase activity, for example, by analysis ofcleavage fragments. A beta can be analyzed by immunoassay, usingspecific detection antibodies. The enzymatic activity is measured in thepresence and absence of the compound inhibitors to demonstrate specificinhibition of beta-secretase mediated cleavage of APP substrate.

Example F

Inhibition of Beta-Secretase in Animal Models of AD

Various animal models can be used to screen for inhibition ofbeta-secretase activity. Examples of animal models useful in theinvention include, but are not limited to, mouse, guinea pig, dog, andthe like. The animals used can be wild type, transgenic, or knockoutmodels. In addition, mammalian models can express mutations in APP, suchas APP695-SW and the like described herein. Examples of transgenicnon-human mammalian models are described in U.S. Pat. Nos. 5,604,102,5,912,410 and 5,811,633.

PDAPP mice, prepared as described in Games et.al., 1995, Nature373:523-527 are useful to analyze in vivo suppression of A beta releasein the presence of putative inhibitory compounds. As described in U.S.Pat. No. 6,191,166, 4 month old PDAPP mice are administered compoundformulated in vehicle, such as corn oil. The mice are dosed withcompound (1-30 mg/ml; preferably 1-10 mg/ml). After time, e.g., 3-10hours, the animals are sacrificed, and brains removed for analysis.

Transgenic animals are administered an amount of the compound inhibitorformulated in a carrier suitable for the chosen mode of administration.Control animals are untreated, treated with vehicle, or treated with aninactive compound. Administration can be acute, i.e., single dose ormultiple doses in one day, or can be chronic, i.e., dosing is repeateddaily for a period of days. Beginning at time 0, brain tissue orcerebral fluid is obtained from selected animals and analyzed for thepresence of APP cleavage peptides, including A beta, for example, byimmunoassay using specific antibodies for A beta detection. At the endof the test period, animals are sacrificed and brain tissue or cerebralfluid is analyzed for the presence of A beta and/or beta-amyloidplaques. The tissue is also analyzed for necrosis.

Animals administered the compound inhibitors of the invention areexpected to demonstrate reduced A beta in brain tissues or cerebralfluids and reduced beta amyloid plaques in brain tissue, as comparedwith non-treated controls.

Example G

Inhibition of A Beta Production in Human Patients

Patients suffering from Alzheimer's Disease (AD) demonstrate anincreased amount of A beta in the brain. AD patients are administered anamount of the compound inhibitor formulated in a carrier suitable forthe chosen mode of administration. Administration is repeated daily forthe duration of the test period. Beginning on day 0, cognitive andmemory tests are performed, for example, once per month.

Patients administered the compound inhibitors are expected todemonstrate slowing or stabilization of disease progression as analyzedby changes in one or more of the following disease parameters: A betapresent in CSF or plasma; brain or hippocampal volume; A beta depositsin the brain; amyloid plaque in the brain; and scores for cognitive andmemory function, as compared with control, non-treated patients.

Example H

Prevention of A Beta Production in Patients at Risk for AD

Patients predisposed or at risk for developing AD are identified eitherby recognition of a familial inheritance pattern, for example, presenceof the Swedish Mutation, and/or by monitoring diagnostic parameters.Patients identified as predisposed or at risk for developing AD areadministered an amount of the compound inhibitor formulated in a carriersuitable for the chosen mode of administration. Administration isrepeated daily for the duration of the test period. Beginning on day 0,cognitive and memory tests are performed, for example, once per month.

Patients administered the compound inhibitors are expected todemonstrate slowing or stabilization of disease progression as analyzedby changes in one or more of the following disease parameters: A betapresent in CSF or plasma; brain or hippocampal volume; amyloid plaque inthe brain; and scores for cognitive and memory function, as comparedwith control, non-treated patients.

It should be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to a composition containing “a compound” includes a mixture oftwo or more compounds. It should also be noted that the term “of” isgenerally employed in its sense including “and/or” unless the contentclearly dictates otherwise.

Unless defined otherwise, all scientific and technical terms used hereinhave the same meaning as commonly understood by one of skill in the artto which this invention belongs.

All patents and publications referred to herein are hereby incorporatedby reference for all purposes.

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A substituted aminoalcohol of formula (I):

or pharmaceutically acceptable salt or ester thereof, wherein B is H,C₁-C₁₀ straight or branched chain alkyl; wherein R₂₀ is H or C₁₋₆ alkylor alkenyl; wherein n is 0 or 1; wherein R₁ is: (I) C₁-C₆ alkyl,optionally substituted with one, two or three substituents selected fromthe group consisting of C₁-C₃ alkyl, C₁-C₇ alkyl (optionally substitutedwith C₁-C₃ alkyl and C₁-C₃ alkoxy), —F, —Cl, —Br, —I, —OH, —SH, —C≡N,—CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H orC₁-C₆ alkyl, —OC═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above, (II) —CH₂—S(O)₀₋₂—(C₁-C₆ alkyl), (III)—CH₂—CH₂—S(O)₀₋₂—(C₁-C₆ alkyl), (IV) C₂-C₆ alkenyl with one or twodouble bonds, optionally substituted with one, two or three substituentsselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆alkyl, (V) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, (VI)—(CH₂)_(n1)—(R_(1-aryl)) where n₁ is zero or one and where R_(1-aryl) isphenyl, 1-naphthyl, 2-naphthyl and indanyl, indenyl, dihydronaphthalyl,tetralinyl optionally substituted with one, two, three or four of thefollowing substituents on the aryl ring: (A) C₁-C₆ alkyl optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b)where R_(1-a) and R_(1-b) are as defined above, —C≡N, —CF₃, C₁-C₃alkoxy, (B) C₂-C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, (C)C₂-C₆ alkynyl with one or two triple bonds, optionally substituted withone, two or three substituents selected from the group consisting of —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a)and R_(1-b) are —H or C₁-C₆ alkyl, (D) —F, Cl, —Br and —I, (F) —C₁-C₆alkoxy optionally substituted with one, two or three —F, (G)NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (H) —OH,(I) —C≡N, (J) C₃-C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of —F, —Cl, —OH,—SH, —C≡N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) andR_(1-b) are —H or C₁-C₆ alkyl, (K) —CO—(C₁-C₄ alkyl), (L)—SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (M)—CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, or(N) —SO₂—(C₁-C₄ alkyl); wherein R₂ is selected from the group consistingof: (I) —H, (II) C₁-C₆ alkyl, optionally substituted with one, two orthree substituents selected from the group consisting of C₁-C₃ alkyl,—F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b)where R_(1-a) and R_(1-b) are as defined above, (III) —(CH₂)₀₋₄—R₂₋₁where R₂₋₁ is R_(1-aryl), where R_(1-aryl) is as defined above, (IV)C₂-C₆ alkenyl with one or two double bonds, optionally substituted withone, two or three substituents selected from the group consisting of —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a)and R_(1-b) are —H or C₁—C₆ alkyl, (V) C₂-C₆ alkynyl with one or twotriple bonds, optionally substituted with one, two or three substituentsselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆alkyl, and (VI) —(CH₂)₀₋₄-C₃-C₇ cycloalkyl, optionally substituted withone, two or three substituents selected from the group consisting of —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a)and R_(1-b) are —H or C₁-C₆ alkyl; wherein R₃ is selected from the groupconsisting of: (I) —H, (II) C₁-C₆ alkyl, optionally substituted withone, two or three substituents selected from the group consisting ofC₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (III)—(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is R_(1-aryl) where R_(1-aryl) is as definedabove, (IV) C₂-C₆ alkenyl with one or two double bonds, (V) C₂-C₆alkynyl with one or two triple bonds, and (VI) —(CH₂)₀₋₄—C₃-C₇cycloalkyl, optionally substituted with one, two or three substituentsselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆alkyl, and where R₂ and R₃ are taken together with the carbon to whichthey are attached to form a carbocycle of three, four, five, six andseven carbon atoms, optionally where one carbon atom is replaced by aheteroatom selected from the group consisting of —O—, —S—, —SO₂—,NR_(1-a), where NR_(1-a) is as defined above; and wherein R_(C) is

wherein R is C₁-C₄ straight or branched chain alkyl optionallysubstituted with —OB or —SO₂B.
 2. A compound according to claim 1,wherein R₁ is —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl), or C₁-C₆ alkyl optionallysubstituted with 1, 2, or 3 groups independently selected from halogen,—OH, ═O, —SH, —C≡N, —CF₃, —C₁-C₃ alkoxy, amino, mono- or dialkylamino,—OC(═O)-amino, -amino-C(═O)O—, and —OC(O)-mono- or dialkylamino, orC₁-C₁₀ alkyl optionally substituted —C₁-C₃ alkoxy, or C₂-C₆ alkenyl orC₂-C₆ alkynyl, each of which is optionally substituted with 1, 2, or 3groups independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, amino, and mono- or dialkylamino, or aryl or —C₁-C₆ alkyl-aryl,where the ring portions of each are optionally substituted with 1, 2, 3,or 4 groups independently selected from halogen, —OH, —SH, —C≡N,—NR₇R′₇, —C(═O)—(C₁-C₄) alkyl, —SO₂-amino, —SO₂-mono or dialkylamino,—C(═O)-amino, —C(═O)-mono or dialkylamino, —SO₂—(C₁-C₄) alkyl, or —C₁-C₆alkoxy optionally substituted with 1, 2, or 3 groups which areindependently a halogen, or C₃-C₇ cycloalkyl optionally substituted with1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N,—CF₃, C₁-C₃ alkoxy, amino, —C₁-C₆ alkyl and mono- or dialkylamino, orC₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups independentlyselected from halogen, —OH, —SH, —C≡N, —CF₃, —C₁-C₃ alkoxy, amino, mono-or dialkylamino and —C₁-C₃ alkyl, or C₂-C₆ alkenyl, alk(di)enyl, C₂-C₆alkynyl or alk(di)ynyl, each of which is optionally substituted with 1,2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N,—CF₃, C₁-C₃ alkoxy, amino, —Cr₁-C₆ alkyl and mono- or dialkylamino.
 3. Acompound according to claim 1, wherein R₁ is: (I) C₁-C₆ alkyl,optionally substituted with one, two or three substituents selected fromthe group consisting of C₁-C₃ alkyl, C₁-C₇ alkyl (optionally substitutedwith C₁-C₃ alkyl and C₁-C₃ alkoxy), —F, —Cl, —Br, —I, —OH, —SH, —C≡N,—CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) are —H or C₁₋₆-C₁₋₆ alkyl, —OC═ONR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (II)—CH₂—S(O)₀₋₂—(C₁-C₆ alkyl), (III) —CH₂-CH₂—S(O)₀₋₂—(C₁-C₆ alkyl), (IV)C₂-C₆ alkenyl with one or two double bonds, optionally substituted withone, two or three substituents selected from the group consisting of —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a)and R_(1-b) are —H or C₁-C₆ alkyl, (V) C₂-C₆ alkynyl with one or twotriple bonds, optionally substituted with one, two or three substituentsselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆alkyl, and (VI) —(CH₂)_(n1)—(R_(1-aryl)) where n₁ is zero or one andwhere R_(1-aryl) is phenyl, 1-naphthyl, 2-naphthyl and indanyl, indenyl,dihydronaphthalyl, tetralinyl optionally substituted with one, two,three or four of the following substituents on the aryl ring: (A) C₁-C₆alkyl optionally substituted with one, two or three substituentsselected from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,—OH, —SH, ≡—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, —C≡N, —CF₃, C₁-C₃ alkoxy, (B) C₂-C₆ alkenyl with one or twodouble bonds, optionally substituted with one, two or three substituentsselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆alkyl, (C) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, (D)—Cl, —Br and —I, (F) —C₁-C₆ alkoxy optionally substituted with one, twoor three —F, (G) NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above, (H) —OH, (I) —C≡N, (J) C₃-C₇ cycloalkyl, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, (K)—CO—(C₁-C₄ alkyl), (L) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)are as defined above, (M) —CO—NR_(1-a) R_(1-b) where R_(1-a) and R_(1-b)are as defined above, or (N) —SO₂—(C₁-C₄ alkyl).
 4. A substitutedaminoalcohol of formula (I):

or a pharmaceutically acceptable salt or ester thereof, wherein B is Hor C₁-C₁₀ straight or branched chain alkyl; R₂₀, R₂ and R₃ are H; n is0; R₁ is 3,5-difluorophenyl; and Rc is

where R is a C₁-C₄ straight or branched chain alkyl group, optionallysubstituted with —OB or —SO₂B.
 5. A method of treating a patient who hasa disease or condition selected from the group consisting of Alzheimer'sdisease, treating or delaying the onset of Alzheimer's disease, and thediffuse Lewy body type of Alzheimer's disease and who is in need of suchtreatment which comprises administration of a therapeutically effectiveamount of a compound selected from the group consisting of a substitutedaminoalcohol according to claim
 1. 6. A compound according to claim 5,wherein R₁ is is —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl), or C₁-C₆ alkyloptionally substituted with 1, 2, or 3 groups independently selectedfrom halogen, —OH, ═O, —SH, —C≡N, —CF₃, —C₁-C₃ alkoxy, amino, mono- ordialkylamino, —OC(═O)-amino, -amino-C(═O)O—, and —OC(═O)-mono- ordialkylamino, or C₁-C₁ alkyl optionally substituted —C₁-C₃ alkoxy, orC₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionally substitutedwith 1, 2, or 3 groups independently selected from halogen, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or dialkylamino, or aryl or—C₁-C₆ alkyl-aryl, where the ring portions of each are optionallysubstituted with 1, 2, 3, or 4 groups independently selected fromhalogen, —OH, —SH, —C≡N, —NR₇R′₇, —C(═O)—(C₁-C₄) alkyl, —SO₂-amino,—SO₂-mono or dialkylamino, —C(═O)-amino,——C(═O)-mono or dialkylamino,—SO₂—(C₁-C₄) alkyl, or —C₁-C₆ alkoxy optionally substituted with 1, 2,or 3 groups which are independently a halogen, or C₃-C₇ cycloalkyloptionally substituted with 1, 2, or 3 groups independently selectedfrom halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, —C₁-C₆ alkyland mono- or dialkylamino, or C₁-C₁₀ alkyl optionally substituted with1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N,—CF₃, —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, orC₂-C₆ alkenyl, alk(di)enyl, C₂-C₆ alkynyl or alk(di)ynyl, each of whichis optionally substituted with 1, 2, or 3 groups independently selectedfrom halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, —C₁-C₆ alkyland mono- or dialkylamino.
 7. A method according to claim 5, wherein R₁is: (I) C₁-C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁-C₃ alkyl, C₁-C₇alkyl (optionally substituted with C₁-C₃ alkyl and C₁-C₃ alkoxy), —F,—Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, —OC═O NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are as defined above, (II) —CH₂—S(O)₀₋₂—(C₁-C₆alkyl), (III) —CH₂-CH₂—S(O)₀₋₂—(C₁-C₆ alkyl), (IV) C₂-C₆ alkenyl withone or two double bonds, optionally substituted with one, two or threesubstituents selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are—H or C₁-C₆ alkyl, (V) C₂-C₆ alkynyl with one or two triple bonds,optionally substituted with one, two or three substituents selected fromthe group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, and(VI) —(CH₂)_(n-1)—(R_(1-aryl)) where n₁ is zero or one and whereR_(1-aryl), is phenyl, 1-naphthyl, 2—naphthyl and indanyl, indenyl,dihydronaphthalyl, tetralinyl optionally substituted with one, two,three or four of the following substituents on the aryl ring: (A) C₁-C₆alkyl optionally substituted with one, two or three substituentsselected from the group consisting of C₁-C₃ alkyl, —F, —Cl, —Br, —I,—OH, —SH, ≡NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, —C≡N, —CF₃, C₁-C₃ alkoxy, (B) C₂-C₆ alkenyl with one or twodouble bonds, optionally substituted with one, two or three substituentsselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁-C₆alkyl, (C) C₂-C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b where R) _(1-a) and R_(1-b) are —H or C₁-C₆ alkyl, (D) —Cl, —Brand —I, (F) —C₁-C₆ alkoxy optionally substituted with one, two or three—F, (G) NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,(H) —OH, (I) —C≡N, (J) C₃-C₇ cycloalkyl, optionally substituted withone, two or three substituents selected from the group consisting of —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a)and R_(1-b) are —H or C₁-C₆ alkyl, (K) —CO—(C₁-C₄ alkyl), (L)—SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (M)—CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, or(N) —SO₂—(C₁-C₄ alkyl).
 8. A method of treating a patient who has adisease or condition selected from the group consisting of Alzheimer'sdisease, treating or delaying the onset of Alzheimer's disease, and thediffuse Lewy body type of Alzheimer's disease and who is in need of suchtreatment which comprises administration of a therapeutically effectiveamount of a compound selected from the group consisting of a substitutedaminoalcohol of the formula (I):

or a pharmaceutically acceptable salt or ester thereof, wherein B is Hor C₁-C₁₀ straight or branched chain alkyl; R₂₀, R₂ and R₃ are H; n is0; R₁ is 3,5-difluorophenyl; and Rc is

where R is a C₁-C₄ straight or branched chain alkyl group, optionallysubstituted with —OB or —SO₂B.
 9. A method for making a compound offormula (I)

or a pharmaceutically acceptable salt or ester thereof, wherein B, R₂₀,R₂, R₃, n and Rc are as defined in claim 1.